Patent Publication Number: US-11649229-B2

Title: Amide compounds for treatment of immune and inflammatory disorders

Description:
BACKGROUND 
     An immune disorder occurs when the immune system is not performing in a normal manner. Inflammation is a protective response that involves immune cells, the immune system generally, blood vessels, and molecular mediators. A wide variety of medical disorders are caused by detrimental immune or inflammatory responses, or the inability of a cell to respond to a normal immune or inflammatory process. 
     The complement system is a part of the innate immune system which does not adapt to changes over the course of the host&#39;s life, but is recruited and used by the adaptive immune system. For example, it assists, or complements, the ability of antibodies and phagocytic cells to clear pathogens. This sophisticated regulatory pathway allows rapid reaction to pathogenic organisms while protecting host cells from destruction. Over thirty proteins and protein fragments make up the complement system. These proteins act through opsonization (enhancing phagocytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cell lysis (rupturing membranes of foreign cells) and agglutination (clustering and binding of pathogens together). 
     The complement system has three pathways: classical, alternative and lectin. Complement Factor D plays an early and central role in activation of the alternative pathway of the complement cascade. Activation of the alternative complement pathway is initiated by spontaneous hydrolysis of a thioester bond within C3 to produce C3(H 2 O), which associates with Factor B to form the C3(H 2 O)B complex. Complement Factor D acts to cleave Factor B within the C3(H 2 O)B complex to form Ba and Bb. The Bb fragment remains associated with C3(H 2 O) to form the alternative pathway C3 convertase C3(H 2 O)Bb. Additionally, C3b generated by any of the C3 convertases also associates with Factor B to form C3bB, which Factor D cleaves to generate the later stage alternative pathway C3 convertase C3bBb. This latter form of the alternative pathway C3 convertase may provide important downstream amplification within all three of the defined complement pathways, leading ultimately to the recruitment and assembly of additional factors in the complement cascade pathway, including the cleavage of C5 to C5a and C5b. C5b acts in the assembly of factors C6, C7, C8, and C9 into the membrane attack complex, which can destroy pathogenic cells by lysing the cell. 
     The dysfunction of or excessive activation of complement has been linked to 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 contributes to the production of C3a and C5a, both potent anaphylatoxins, which also have roles in a number of inflammatory disorders. Therefore, in some instances, it is desirable to decrease the response of the complement pathway, including the alternative complement pathway. Some examples of disorders mediated by the complement pathway include age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis, and rheumatoid arthritis. 
     Age-related macular degeneration (AMD) is a leading cause of vision loss in industrialized countries. Based on a number of genetic studies, there is evidence of the link 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. Individuals with mutant Factor H also have increased levels of C-reactive protein, a marker of inflammation. Without adequate functioning Factor H, the alternative pathway of the complement cascade is overly activated leading to cellular damage. Inhibition of the alternative pathway is thus desired. 
     Paroxysmal nocturnal hemoglobinuria (PNH) is a non-malignant, hematological disorder characterized by the expansion of hematopoietic stem cells and progeny mature blood cells which are deficient in some surface proteins. PNH erythrocytes are not capable of modulating their surface complement activation, which leads to the typical hallmark of PNH—the chronic activation of complement mediated intravascular anemia. Currently, only one product, the anti-C5 monoclonal antibody eculizumab, has been approved in the U.S. for treatment of PNH. However, many of the patients treated with eculizumab remain anemic, and many patients continue to require blood transfusions. In addition, treatment with eculizumab requires life-long intravenous injections. Thus, there is an unmet need to develop novel inhibitors of the complement pathway. 
     Other disorders that have been linked to the complement cascade include atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, or hemodialysis, neuromylitis (NMO), myasthenia gravis (MG), fatty liver, nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, liver failure, dermatomyocitis, and amyotrophic lateral sclerosis. 
     Factor D is an attractive target for inhibition or regulation of the complement cascade due to its early and essential role in the alternative complement pathway, and its potential role in signal amplification within the classical and lectin complement pathways. Inhibition of Factor D effectively interrupts the pathway and attenuates the formation of the membrane attack complex. 
     While initial attempts have been made to develop inhibitors of Factor D, there are currently no small molecule Factor D inhibitors in clinical trials. Examples of Factor D inhibitors or prolyl compounds are described in the following disclosures. 
     Biocryst Pharmaceuticals U.S. Pat. No. 6,653,340 titled “Compounds useful in the complement, coagulate and kallikrein pathways and method for their preparation” describes fused bicyclic ring compounds that are potent inhibitors of Factor D. Development of the Factor D inhibitor BCX1470 was discontinued due to lack of specificity and short half-life of the compound. Novartis PCT patent publication WO2012/093101 titled “Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration” describes certain Factor D inhibitors. Additional Factor D inhibitors are described in Novartis PCT patent publications WO2014/002051, WO2014/002052, WO2014/002053, WO2014/002054, WO2014/002057, WO2014/002058, WO2014/002059, WO2014/005150, and WO2014/009833. 
     Bristol-Myers Squibb PCT patent publication WO2004/045518 titled “Open chain prolyl urea-related modulators of androgen receptor function” describes open chain prolyl urea and thiourea related compounds for the treatment of androgen receptor-associated conditions, such as age-related diseases, for example, sarcopenia. 
     Japan Tobacco Inc. PCT patent publication WO1999/048492 titled “Amide derivatives and nociceptin antagonists” describes compounds with a proline-like core and aromatic substituents connected to the proline core through amide linkages useful for the treatment of pain. 
     Ferring B. V. and Yamanouchi Pharmaceutical Co. lTD. PCT patent publication WO1993/020099 titled “CCK and/or gastrin receptor ligands” describes compounds with a proline-like core and heterocyclic substituents connected to the proline core through amide linkages for the treatment of, for example, gastric disorders or pain. 
     Alexion Pharmaceuticals PCT patent publication WO1995/029697 titled “Methods and compositions for the treatment of glomerulonephritis and other inflammatory diseases” discloses antibodies directed to C5 of the complement pathway for the treatment of glomerulonephritis and inflammatory conditions involving pathologic activation of the complement system. Alexion Pharmaceutical&#39;s anti-05 antibody eculizumab (Soliris®) is currently the only complement-specific antibody on the market, and is the first and only approved treatment for paroxysmal nocturnal hemoglobinuria (PNH). 
     On Feb. 25, 2015, Achillion Pharmaceuticals filed PCT Patent Application No. PCT/US2015/017523 and U.S. patent application Ser. No. 14/631,090 titled “Alkyne Compounds for Treatment of Complement Mediated Disorders”; PCT Patent Application No. PCT/US2015/017538 and U.S. patent application Ser. No. 14/631,233 titled “Amide Compounds for Treatment of Complement Mediated Disorders”; PCT Patent Application No. PCT/US2015/017554 and U.S. patent application Ser. No. 14/631,312 titled “Amino Compounds for Treatment of Complement Mediated Disorders”; PCT Patent Application No. PCT/US2015/017583 and U.S. patent application Ser. No. 14/631,440 titled “Carbamate, Ester, and Ketone Compounds for Treatment of Complement Mediated Disorders”; PCT Patent Application No. PCT/US2015/017593 and U.S. patent application Ser. No. 14/631,625 titled “Aryl, Heteroaryl, and Heterocyclic Compounds for Treatment of Complement Mediated Disorders”; PCT Patent Application No. PCT/US2015/017597 and U.S. patent application Ser. No. 14/631,683 titled “Ether Compounds for Treatment of Complement Mediated Disorders”; PCT Patent Application No. PCT/US2015/017600 and U.S. patent application Ser. No. 14/631,785 titled “Phosphonate Compounds for Treatment of Complement Mediated Disorders”; and PCT Patent Application No. PCT/US2015/017609 and U.S. patent application Ser. No. 14/631,828 titled “Compounds for Treatment of Complement Mediated Disorders” and U.S. patent application Ser. No. 14/630,959 titled “Factor D Inhibitors Useful for Treating Infectious Disorders.” 
     Given the wide variety of medical disorders that are caused by detrimental immune or inflammatory responses, new uses and compounds are needed for medical treatment. In one aspect, new uses and compounds are needed to mediate the complement pathway, and for example, which act as Factor D inhibitors for treatment of disorders in a host, including a human, associated with misregulation of the complement cascade, or with undesired result of the complement cascade performing its normal function. 
     SUMMARY 
     This invention includes an active compound of Formula I, Formula I′ or Formula I″ or a pharmaceutically acceptable salt or composition thereof, wherein at least one of R 12  or R 13  on the A group is an amide substituent, for example R 32 . In one embodiment, an active compound or its salt or composition, as described herein is used to treat a medical disorder which 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 ability of the cell to engage in or respond to normal complement activity, or an undesired complement-mediated response to a medical treatment, such as surgery or other medical procedure or a pharmaceutical or biopharmaceutical drug administration, a blood transfusion, or other allogenic tissue or fluid administration. 
     These compounds can be used to treat such condition in a host in need thereof, typically a human. The active compound may act as an inhibitor of the complement factor D cascade. In one embodiment, a method for the treatment of such a disorder is provided that includes the administration of an effective amount of a compound of Formula I, Formula I′ or Formula I″ or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, as described in more detail below. 
     In one embodiment, the disorder is associated with the alternative complement cascade pathway. In yet another embodiment, the disorder is associated with the complement classical pathway. In a further embodiment, the disorder is associated with the complement lectin pathway. Alternatively, the active compound or its salt or prodrug may act through 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 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) is provided that includes the administration of an effective amount of a compound to a host of Formula I, Formula I′ or Formula I″ or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, a method for the treatment of wet or dry age-related macular degeneration (AMD) in a host is provided that includes the administration of an effective amount of a compound of Formula I, Formula I′ or Formula I″ or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, a method for the treatment of rheumatoid arthritis in a host is provided that includes the administration of an effective amount of a compound of Formula I, Formula I′ or Formula I″ or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, a method for the treatment of multiple sclerosis in a host is provided that includes the administration of an effective amount of a compound of Formula I, Formula I′ or Formula I″ or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. 
     In other embodiments, an active compound or its salt or prodrug as described herein can be used to treat fatty liver and conditions stemming from fatty liver, nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, and liver failure, dermatomyocitis, or amyotrophic lateral sclerosis. 
     The active compound or its pharmaceutically acceptable salt, prodrug or a pharmaceutical composition thereof as disclosed herein is also useful for administration in combination or alternation with a second pharmaceutical agent for use in ameliorating or reducing a side effect of the second pharmaceutical agent. For example, in one embodiment, the active compound may be used in combination with an adoptive cell transfer therapy to reduce an 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 T-Cell (CAR T) or a dendritic cell used to treat a hematologic or solid tumor, for example, a B-cell related hematologic cancer. In one embodiment, the hematologic or solid tumor is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin&#39;s lymphoma, chronic lymphocytic leukemia (CLL), pancreatic cancer, glioblastoma, or a cancer that expresses CD19. In one embodiment, the associated inflammatory response is a cytokine mediated response. 
     Another embodiment is provided that includes the administration of an effective amount of an active compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier to a host to treat an ocular, pulmonary, gastrointestinal, or other disorder that can benefit from topical or local delivery. 
     Any of the compounds described herein (Formula I, Formula I′ or Formula I″) can be administered to the eye in any desired form of administration, including via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachoroidal, choroidal, subchoroidal, conjunctival, subconjunctival, episcleral, posterior juxtascleralscleral, circumcorneal, and tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion. 
     In other embodiments of the invention, an active compound provided herein can be used to treat or prevent a disorder in a host mediated by complement factor D, or by an excessive or detrimental amount of the complement-C3 amplification loop of the complement pathway. As examples, the invention includes methods to treat or prevent complement associated disorders that are induced by antibody-antigen interactions, a component of an immune or autoimmune disorder or by ischemic injury. The invention also provides methods to decrease inflammation or an immune response, including an autoimmune response, where mediated or affected by factor D. 
     In another embodiment, a method is provided for treating a host, typically a human, with a disorder mediated by the complement system, that includes administration of a prophylactic antibiotic or vaccine to reduce the possibility of a bacterial infection during the treatment using one of the compounds described herein. In certain embodiments, the host, typically a human, is given a prophylactic vaccine prior to, during or after treatment with one of the compounds described herein. In certain embodiments, the host, typically a human, is given a prophylactic antibiotic prior to, during or after treatment with one of the compounds described herein. In some embodiment, the infection is a meningococcal infection (e.g., septicemia and/or meningitis), an  Aspergillus  infection, or an infection due to an encapsulated organism, for example,  Streptococcus pneumoniae  or  Haemophilus influenza  type b (Hib), especially in children. In other embodiments, the vaccine or antibiotic is administered to the patient after contracting an infection due to, or concommitent with inhibition of the complement system. 
     The disclosure provides a compound of Formula I: 
                         
or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof.
 
     A is selected from A1, A1′ and A2. 
     B is selected from B1, B1′, B2, B3, and B4. 
     C is selected from C1, C1′, C2, C3, and C4. 
     L is selected from L1, L1′, L2, and L2′. 
     L3 is selected from L4 and L5. 
     At least one of A, B, C, L, or L3 is selected from A2, B3, C3, L2, L2′, or L5. 
     Or at least one of A, B, C, L, or L3 is selected from A2, B3, C4, L2, L2′, or L5 
     If C is C1, C1′ or C2, then Formula I includes at least one of A2, B3, L2, L2′ or L5. 
     If C is C3, then Formula I can be any of A, B, L or L3. 
     C1 is 
     
       
         
         
             
             
         
       
     
     Q 1  is N(R 1 ) or C(R 1 R 1′ ). 
     Q 2  is C(R 2 R 2′ ), C(R 2 R 2′ )—C(R 2 R 2′ ), S, O, N(R 2 ) or C(R 2 R 2′ )O. 
     Q 3  is N(R 3 ), S, or C(R 3 R 3′ ). 
     X 1  and X 2  are independently N, CH, or CZ, or X 1  and X 2  together are C═C. 
     Q 1 , Q 2 , Q 3 , X 1 , and X 2  are selected such that a stable compound results. 
     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 at each occurrence, as appropriate, and only where a stable compound results, from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkynyl, C 2 -C 6 alkanoyl, C 1 -C 6 thioalkyl, 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 , C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy. 
     R 9  and R 10  are independently selected at each occurrence from hydrogen, 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). 
     In alternative embodiments, R 1  and R 1′  or R 3  and R 3′  may be 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; R 2  and R 2′  may be taken together to form a 3- to 6-membered carbocyclic spiro ring; or R 2  and R 2′  may be taken together to form a 3- to 6-membered heterocyclic spiro ring; each of which spiro ring each of which ring may be unsubstituted or substituted with 1 or more substituents independently selected from halogen (and in particular F), hydroxyl, cyano, —COOH, C 1 -C 4 alkyl (including in particular methyl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 2 -C 4 alkanoyl, hydroxyC 1 -C 4 alkyl, (mono- and di-C 1 -C 4 alkylamino)C 0 -C 4 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —O—C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy. 
     In alternative embodiments, R 1  and R 2  may be taken together to form a 3-membered carbocyclic ring; R 1  and R 2  may be taken together to form 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 , if bound to adjacent carbon atoms, may be taken together to form a 3- to 6-membered carbocyclic or aryl ring or a 3- to 6-membered heterocyclic or heteroaryl ring; each of which ring may be unsubstituted or substituted with 1 or more substituents independently selected from halogen (and in particular F), hydroxyl, cyano, —COOH, C 1 -C 4 alkyl (including in particular methyl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 2 -C 4 alkanoyl, hydroxyC 1 -C 4 alkyl, (mono- and di-C 1 -C 4 alkylamino)C 0 -C 4 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —O—C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy. 
     In alternative embodiments, R 1  and R 1′ , R 2  and R 2′ , or R 3  and R 3′  can be taken together to form a carbonyl group. In alternative embodiments, R 1  and R 2  or R 2′  and R 3  can be taken together to form a carbon-carbon double bond. 
     Any of the structures illustrated herein, e.g., A1, A1′, A2, B1, B1′, B2, B3, B4, C1, C1′, C2, C3, L1, L1′, L2, L4 or L5 can be optionally substituted with 0, 1, 2, 3, or 4, as appropriate, and independently, of an R 48  substituent. 
     Non-limiting examples of C1 include the structures of  FIG.  1   , wherein R and R′ (see  FIG.  5   ) are independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl wherein each group can be optionally substituted or any other substituent group herein that provides the desired properties. In some embodiments, the ring includes one or more chiral carbon atoms. The invention includes embodiments in which the chiral carbon can be provided as an enantiomer, or mixtures of enantiomers, including a racemic mixture. Where the ring includes more than one stereocenter, all of the enantiomers and diastereomers are included in the invention as individual species, unless stereochemistry is specified. 
     In one embodiment, C1 is C1′. 
     Non-limiting examples of C1′ include the structures of  FIG.  2   . 
     In one embodiment, a methyl group in a structure illustrated in  FIG.  2    can be replaced with a different alkyl group, as defined herein. In another embodiment, the fluoro atoms in the structures illustrated in  FIG.  2    can be replaced with any other halogen. As indicated above, any of the structures illustrated in  FIG.  2    or otherwise can be optionally substituted with 0, 1, 2, 3, or 4, as appropriate, and independently, with an R 48  substituent. 
     C2 is selected from: 
                         
wherein q is 0, 1, 2 or 3 and r is 1, 2 or 3.
 
     R 44 , R 44′ , R 45 , are independently hydrogen, hydroxyl, amino, cyano, halogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; wherein each group can be optionally substituted, and such that a stable C2 results. 
     In one embodiment, R 44  and R 44′ , R 45  and R 45′  or two R 47  groups can be taken together to form a carbonyl group. 
     In an alternate embodiment, R 44  and R 44′  or R 45  and R 45′  or R 46  and R 46′  can be 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. 
     In one embodiment, R 44  and R 45  or R 44′  and R 45′  can be 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 ring may be unsubstituted or substituted with 1 or more substituents. 
     Non-limiting examples of C2 include the structures of  FIG.  3   . 
     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′ ). 
     In alternative embodiments, X 4  and X 5  or X 5  and X 6  together are C═C. 
     X 7  is SO or SO 2 . 
     X 8  is C(R 1 R 1′ ) or N(R 43 ). 
     X 5′  is C(R 1 R 1′ ) or O. 
     Q 4  is N or CH. 
     Q 5  is N(R 47 ) or C(R 46 R 46′ ). 
     Q 5a  is C(R 47 R 47 ), N(R 47 ), O, S, SO, or 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 each independently C(R 2 R 2′ ), S, SO, SO 2 , O, N(R 2 ), B(R 50 ), Si(R 49 ) 2 , however if X 1  is N and X 2  is CH then L and B taken together cannot be anisole substituted in the 4 position. 
     In a typical embodiment, no more than one heteroatom is in a three or four membered C3 and no more than one, two or three heteroatoms can be in a five, six or seven membered C3. It is in general known by those of skill in the art which combinations of several heteroatoms will not form a stable ring system. For example, those of skill in the art would understand that the C3 ring system would not normally contain an —O—O—, —O—S—, —Si—Si—, —B—B—, —B—Si—, bond. 
     R 40  is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl wherein each group can be optionally substituted. 
     R 42  is halo, hydroxy, C 1 -C 6 alkoxy, 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, heteroarylalkyl wherein each group can be optionally substituted. 
     R 46  and R 46′  are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl wherein each group can be optionally substituted and at least one of R 46  or R 46′  is not hydrogen. 
     R 47  is hydrogen, acyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl wherein each group can be optionally substituted. 
     R 49  is halo, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl wherein each group can be optionally substituted or two R 49  groups can be taken together to form a double bond that can be optionally substituted. 
     R 50  is hydroxy or C 1 -C 6 alkyoxy. 
     In one embodiment, the bridged heterocyclic C3 compounds can be optionally substituted. 
     In one embodiment, 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  can form a carbon-carbon double bond. 
     In one embodiment, two Q 5 a groups or a X 4 a and a Q 5 a group can form a carbon-carbon double bond. 
     All variables, including but not limited to X 1 , X 2 , X 3 , X 4 , X 5 , X 5a , X 6 , X 7 , X 8 , Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7 , Q 8 , Q 9 , Q 10 , Q 11 , Q 12 , R 1 , R 40 , R 42 , R 43 , R 44 , R 44′ , R 45 , and R 45′  are independently selected at each occurrence, as appropriate, and only where a stable compound results. For example, when C3 is a 7-membered ring and comprises silicon or boron, the ring will only comprise one Si(R 49 ) 2  or B(R 50 ) moiety. In addition, 3, 4, 5, 6 and 7-membered rings will not comprise —O—O— or —O—S— bonds. 
     Non-limiting examples of C3 include the structures of  FIG.  4   . 
     In one embodiment, the methyl groups in the structures illustrated in  FIG.  4    can be replaced with a different alkyl group, as defined herein. In another embodiment, the fluoro atoms in the structures illustrated above can be replaced with another halo. In another embodiment, halo can be chloro. As indicated above, any of the structures in  FIG.  4    or herein can be optionally substituted with 0, 1, 2, 3, or 4, as appropriate, and independently, with an R 48  substituent. 
     In an alternate embodiment, the central core moiety, C3, can comprise a small mimetic of a beta-turn such as a benzodiazepine, a Friedinger lactam, a 2-oxo-1,3-oxazolidine-4-caroxylate or a β-D-glucose scaffold. 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 moiety, C, can comprise a reverse turn mimetic that can include, but is not limited to; a non-peptidic residue, a metal chelation based mimic, or a foldamer. See, Nair, R. V. et al., “Synthetic turn mimetics and hairpin nucleators: Quo Vadimus?”, Chem. Comm., 2014, 50, 13874-13884. In some embodiments, the central core moiety, C, can comprise a conformationally constrained cyclic amino acid including but not limited to a (S)- or (R)-α-trifluoromethyl pyroglutamic acid derivative. 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 some embodiments, the central core moiety, C, can comprise a monomeric unit of a foldamer such as, but not limited to an oxazolidin-2-one. See, Tomasii, C., Angelicim G. and Castellucci, N., “Foldamers Based on Oxazolidin-2-ones”, Eur. J. Org. Chem., 2011, 3648-3669. 
     Examples of central core small mimetics of a beta-turn, beta turn inducers, reverse turn mimetics and foldamer monomers include, but are not limited to the structures of  FIG.  5   . 
     C4 is selected from 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     R 101  is C 1 -C 4  alkyl or C 3 -C 7  cycloalkyl. 
     R 102  is C 1 -C 4  alkyl, fluorine, chlorine, or bromine. 
     Non-limiting examples of C4 include: 
     
       
         
         
             
             
         
       
     
     A1 is selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Non-limiting examples of A1 include: 
     
       
         
         
             
             
         
       
     
     In one embodiment, A1 is A1′. 
     Non-limiting examples of A1′ include the structures of  FIG.  6   . 
     A2 is selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Non-limiting examples of A2 include the structures of  FIG.  7   . 
     In one embodiment, additional examples include compounds wherein the 2-methyl pyrimidine is replaced with a R 32  moiety. 
     R 4  is selected from -JCHO, -JCONH 2 , JC 2 -C 6 alkanoyl, hydrogen, -JSO 2 NH 2 , -JC(CH 2 ) 2 F, -JCH(CF 3 )NH 2 , 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 , 
                         
each of which R 4  other than hydrogen, or —CHO, is unsubstituted or substituted with one or more of amino, imino, halogen, hydroxyl, cyano, cyanoimino, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, —C 0 -C 2 alkyl(mono- and di-C 1 -C 4 alkylamino), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.
 
     R 4′  is selected from -JCHO, -JCONH 2 , JC 2 -C 6 alkanoyl, hydrogen, -JSO 2 NH 2 , -JC(CH 2 ) 2 F, -JCH(CF 3 )NH 2 , 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 , 
                         
each of which R 4′  other than —CHO, is unsubstituted or substituted with one or more of amino, imino, halogen, hydroxyl, cyano, cyanoimino, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, —C 0 -C 2 alkyl(mono- and di-C 1 -C 4 alkylamino), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.
 
     R 5  and R 6  are independently selected from —CHO, —C(O)NH 2 , —C(O)NH(CH 3 ), C 2 -C 6 alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, —COOH, —SO 2 NH 2 , vinyl, C 1 -C 6 alkyl (including methyl), C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —C(O)C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —P(O)(OR 9 ) 2 , —OC(O)R 9 , —C(O)OR 9 , —C(O)N(CH 2 CH 2 R 9 )(R 10 ), —NR 9 C(O)R 10 , phenyl, or 5- to 6-membered heteroaryl. In one embodiment, R 5  and R 6  are each independently —C 0 -C 4 alkyl(C 3 -C 7 heterocycloalkyl), SO 2 (C 1 -C 6 alkyl), SO 2 (C 1 -C 6 haloalkyl), SO 2 NR 7 R 7 , SO═NH(C 1 -C 6 alkyl), 
                         
-J-C 2 -C 6 alkanoyl, -J-C(O)NH 2 , -J-SO 2 NH 2 , —C(O)NH(CH 3 ), -J-COOH, -J-C(O)C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), -JP(O)(OR 9 ) 2 , -J-OC(O)R 9 , -J-C(O)OR 9 , -J-C(O)N(CH 2 CH 2 R 9 )(R 10 ), -JNR 9 C(O)R 10 , -J-phenyl, or -J-(5- to 6-membered heteroaryl) that can be optionally substituted.
 
     Each R 5  and R 6  other than hydrogen, hydroxyl, cyano, and —COOH is unsubstituted or optionally substituted. For example, R 5  and R 6  other than hydrogen, hydroxyl, cyano, and —COOH may be substituted with one or more substituents independently selected from halogen, hydroxyl, amino, imino, cyano, cyanoimino, C 1 -C 2 alkyl, C 1 -C 4 alkoxy, —C 0 -C 2 alkyl(mono- and di-C 1 -C 4 alkylamino), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy. 
     R 6′  is 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  is hydrogen, C 1 -C 6 alkyl, or —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl). 
     R 8  and R 8′  are independently selected from hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), 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′  can be taken together with the carbon that they are bonded to form a 3-membered carbocyclic ring. 
     R 16  is absent or is independently selected from halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, 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), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy. 
     R 19  is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, 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), C 0 -C 4 alkyl(heteroaryl), and wherein R 19  other than hydrogen is unsubstituted or 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 . 
     No more than 2 of X 11 , X 12 , X 13 , and X 14  are N. 
     One of R 12  and R 13  is selected from R 31  and the other of R 12  and R 13  is selected from R 32 , however, each compound has at least one R 32 . In an alternative embodiment, R 12  and R 13  are each independently selected from an R 32  moiety. 
     R 31  is selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, —COOH, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, —C(O)OR 9 , 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 which R 31  other than hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, —COOH, —CONH 2  C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy, and each of which R 31  is also optionally substituted with one substituent selected from phenyl and 4- to 7-membered heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; which phenyl or 4- to 7-membered heterocycle is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, (mono- and di-C 1 -C 6 alkylamino)C 0 -C 4 alkyl, C 1 -C 6 alkylester, —C 0 -C 4 alkyl)(C 3 -C 7 cycloalkyl), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy. 
     R 32  is selected from C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , each of which can be optionally substituted. 
     R 11 , R 14 , and R 15  are independently selected at each occurrence from hydrogen, halogen, hydroxyl, nitro, cyano, —O(PO)(OR 9 ) 2 , —(PO)(OR 9 ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, 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, C 2 -C 6 alkynyl(aryl), C 2 -C 6 alkynyl(cycloalkyl), C 2 -C 6 alkynyl(heterocycle), C 2 -C 6 alkynyl(heteroaryl), C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, 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), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy. 
     X 15  is 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  and X 25  are each independently 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  is —CO— or —SO— or —SO 2 —. 
     X 34  is CHR 13 , NH, O, or S. 
     No more than 2 of X 28  are N. 
     R 30  is independently selected at each occurrence from hydrogen, C 1 -C 6 alkyl, 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 7-membered heterocycloalkyl)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; (5- or 6-membered unsaturated or aromatic heterocycle)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; COOH, Si(CH 3 ) 3 , COOR 30a , C 2 -C 6 alkanoyl, —B(OH) 2 , —C(O)(CH 2 ) 1-4 S(O)R 21 , —P(O)(OR 21 )(OR 22 ), —P(O)(OR 21 )R 22 , —P(O)R 21 R 22 , —NR 9 P(O)(NHR 21 )(NHR 22 ), —NR 9 P(O)(OR 21 )(NHR 22 ), —NR 9 P(O)(OR 21 )(OR 22 ), —C(S)R 21 , —NR 21 SO 2 R 22 , —NR 9 S(O)NR 10 R 22 , —NR 9 SO 2 NR 10 R 22 , —SO 2 NR 9 COR 22 , —SO 2 NR 9 CONR 21 R 22 , —NR 21 SO 2 R 22 , —C(O)NR 21 SO 2 R 22 , —C(NH 2 )NR 9 R 22 , —C(NH 2 )NR 9 S(O) 2 R 22 , —NR 9 C(O)OR 10 , —NR 21 OC(O)R 22 , —(CH 2 ) 1-4 C(O)NR 21 R 22 , —C(O)R 24 R 25 , —NR 9 C(O)R 21 , —C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 24 R 25 , —(CH 2 ) 1-4 OC(O)R 21 , each of which R 30  can be optionally substituted. 
     R 41  is hydrogen, C 1 -C 6 alkyl, or —(C 0 -C 2 alkyl)(C 3 -C 5 cycloalkyl). 
     R 48  is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 thioalkyl, 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 25 , -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 ; each of which R 48  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, —CONH 2 , —P(O)(OH) 2 , 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 ), C 1 -C 6 alkylester, C 1 -C 4 alkylamino, C 1 -C 4 hydroxylalkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, —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 , C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy. 
     R 48a  is R 48 , S(O)═NHR 21 , SF 5 , and JC(R 9 )═NR 21  and SO 2 OR 21 . 
     R 54  is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkynyl, C 2 -C 6 alkanoyl, 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 and (heteroaryl)C 0 -C 4 alkyl- wherein the groups can be optionally substituted. 
     R 71  is selected at each occurrence from hydroxyl, 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 7-membered heterocycloalkyl)C 0 -C 4 alkyl having 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 having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and each can be optionally substituted. 
     s is 1 or 2. 
     L is selected from L1, L1′, L2, and L2′. 
     L1 is a bond or is selected from the formulas 
     
       
         
         
             
             
         
       
     
     R 17  is hydrogen, C 1 -C 6 alkyl, or —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl) and R 18  and R 18′  are independently selected from hydrogen, halogen, hydroxymethyl, and methyl; and m is 0, 1, 2, or 3. 
     In one embodiment, L1 is L1′. 
     Non-limiting examples of L1′ include the structures of  FIG.  8   . 
     In one embodiment, the methyl groups in the structures illustrated in  FIG.  8    can be replaced with another alkyl group, as defined herein. 
     L2 is selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Or an optionally substituted monocyclic or bicyclic carbocyclic; an optionally substituted monocyclic or bicyclic carbocyclic-oxy group; an optionally substituted monocyclic or bicyclic heterocyclic group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and from 4 to 7 ring atoms per ring, an optionally substituted —(C 0 -C 4 alkyl)(aryl); an optionally substituted —(C 0 -C 4 alkyl)(5-membered heteroaryl) selected from pyrrole, furan, thiophene, pyrazole, oxazole, isoxazole, thiazole and isothiazole or a substituted imidazole; an optionally substituted —(C 0 -C 4 alkyl)(6-membered heteroaryl); an optionally substituted —(C 0 -C 4 alkyl)(8-membered heteroaryl); an optionally substituted —(C 0 -C 4 alkyl)(9-membered heteroaryl) selected from isoindole, indazole, purine, indolizine, benzothiophene, benzothiazole, benzoxazole, benzofuran, and furopyridine; and —(C 0 -C 4 alkyl)(10-membered heteroaryl); q is 1, 2 or 3. 
     L2′ is selected from: 
                                           
wherein R 51  is CH 3 , CH 2 F, CHF 2  or CF 3 .
 
     wherein R 53  is cyano, nitro, hydroxyl or C 1 -C 6 alkoxy. 
     X 29  can be O or S. 
     In certain embodiment, L2 is a bond. In certain embodiments, if L2 is heterocyclic or heteroaryl, then B can be hydrogen. 
     Non-limiting examples of L2 include the structures of  FIG.  9   . 
     In one embodiment, the methyl groups in the structures illustrated in  FIG.  9    can be replaced with another alkyl or an acyl, as defined herein. In another embodiment, the carbocyclic, heterocyclic, aryl or heteroaryl rings can be optionally substituted. As indicated above, any of the structures illustrated in  FIG.  9    or herein can be optionally substituted with 0, 1, 2, 3, or 4, as appropriate, and independently, of an R 48  substituent. 
     L3 is selected from L4 or L5. 
     L4 is —C(O)—. 
     L5 is —C(S)—, —P(O)OH—, —(O)—, —S(O) 2 — or —C(R 52 ) 2 —, wherein each R 52  is independently selected from halo, hydrogen, or optionally substituted C 1 -C 6 alkyl. In certain embodiments the two R 52  groups can be 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 a monocyclic or bicyclic carbocyclic; a monocyclic or bicyclic carbocyclic-oxy group; a monocyclic, bicyclic, or tricyclic heterocyclic group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and from 4 to 7 ring atoms per ring; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; —(C 0 -C 4 alkyl)(aryl); —(C 0 -C 4 alkyl)(heteroaryl); or —(C 0 -C 4 alkyl)(biphenyl), each of which B1 is unsubstituted or substituted with one or more substituents independently selected from R 33  and R 34 , and 0 or 1 substituents selected from R 35  and R 36 . 
     R 33  is independently selected from halogen, hydroxyl, —COOH, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, —C 0 -C 4 alkylNR 9 R 10 , —SO 2 R 9 , C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy. 
     R 34  is independently selected from nitro, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 thioalkyl, -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)R 24 R 25 , -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 , and -JC(O)OR 23 ; each of which R 34  may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH) 2 , —S(CH 3 ) 3 , —COOH, —CONH 2 , —P(O)(OH) 2 , C 1 -C 6 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), C 1 -C 6 alkoxy, —C 0 -C 2 alkyl(mono- and di-C 1 -C 4 alkylamino), C 1 -C 6 alkylester, C 1 -C 4 alkylamino, C 1 -C 4 hydroxylalkyl, C 1 -C 2 haloalkyl, and C 1 -C 2 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 bicyclic heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and containing 4- to 7-ring atoms in each ring; each of which R 35  is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, (mono- and di-C 1 -C 6 alkylamino)C 0 -C 4 alkyl, C 1 -C 6 alkylester, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —SO 2 R 9 , C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy. 
     R 36  is independently selected from tetrazolyl, (phenyl)C 0 -C 2 alkyl, (phenyl)C 1 -C 2 alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, B, and S, each of which R 36  is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, (mono- and di-C 1 -C 6 alkylamino)C 0 -C 4 alkyl, C 1 -C 6 alkylester, —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 , C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy. 
     In one additional alternative embodiment B is selected from: 
     
       
         
         
             
             
         
       
     
     In one additional alternative embodiment R 36  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 . 
     R 21  and R 22  are independently selected at each occurrence from hydrogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 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 7-membered heterocycloalkyl)C 0 -C 4 alkyl having 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 having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and each R 21  and R 22  can be optionally substituted. In one embodiment, R 21  and R 22  can be taken together to form a carbocyclic or heterocyclic ring. 
     R 23  is independently selected at each occurrence from C 1 -C 6 alkyl, 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 7-membered heterocycloalkyl)C 0 -C 4 alkyl having 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 having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and each R 23  can be optionally substituted. 
     R 24  and R 25  are taken together with the nitrogen to which they are attached to form a 4- to 7-membered monocyclic heterocycloalkyl group, or a 6- to 10-membered bicyclic heterocyclic group having fused, spiro, or bridged rings, and each R 24  and R 25  can be optionally substituted. 
     J is independently selected at each occurrence from a covalent bond, C 1 -C 4 alkylene, —OC 1 -C 4 alkylene, C 2 -C 4 alkenylene, and C 2 -C 4 alkynylene. 
     In one embodiment, B1 is selected from the structures of  FIG.  10   , wherein R 27  is 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 ) 3 . 
     In one embodiment, B1 is B1′. Non-limiting examples of B1′ include the structures of  FIGS.  11    A-D. 
     Examples of B moieties include, but are not limited to 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In one embodiment, B is B2 which is selected from the structures of  FIG.  12   . 
     In one embodiment B3 is:
         (I) a monocyclic or bicyclic carbocyclic; a monocyclic or bicyclic carbocyclic-oxy group; a monocyclic, bicyclic, or tricyclic heterocyclic group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and from 4 to 7 ring atoms per ring; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; —(C 0 -C 4 alkyl)(aryl); —(C 0 -C 4 alkyl)(heteroaryl); or —(C 0 -C 4 alkyl)(biphenyl); each of which B3 is substituted with one or more of the following: S(O)═NHR 21 , SF 5 , and JC(R 9 )═NR 21 ;   (II) a monocyclic, bicyclic, or tricyclic heterocyclic group that has at least one boron or silicon atom in the ring or a monocyclic, bicyclic, or tricyclic heteroaryl group that has at least one boron in the ring;   (III) a 6-membered aryl group fused to a 5-membered saturated cyclic group that optionally contains 1 or 2 heteroatoms independently selected from N and S wherein one of the CH 2  groups of the 5-membered cyclic group is optionally substituted by oxo (i.e., ═O) excluding dihydrobenzofuran;   (IV) an 8-membered monocyclic or bicyclic heteroaryl, however; when A is A1 or A1′; C is C1, C1′ or C2; L is L1 or L1′ and L3 is L4 the following species are excluded: 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole.   (V) a 9-membered monocyclic or bicyclic heteroaryl group, however; when A is A1 or A1′; C is C1, C1′ or C2; L is L1 or L1′ and L3 is L4 the following species are excluded: 6-chloro-1H-benzo[d]imidazole bonded at the 7 position, 6-fluoro-1H-benzo[d]imidazole bonded at the 7 position, 6-(methylthio)-1H-benzo[d]imidazole bonded at the 7 position, and 6-(methoxy)-1H-benzo[d]imidazole bonded at the 7 position, 7-chloro-imidazo[1,2-a]pyridine substituted at the eight position, 7-(methylthio)-imidazo[1,2-a]pyridine substituted at the eight position, 7-fluoro-imidazo[1,2-a]pyridine substituted at the eight position, 7-methoxyimidazo[1,2-a]pyridine substituted at the eight position, 4-fluoro-1H-indole substituted at the 4 position, [1,2,4]triazole[4,3-a]pyridine substituted at the 2 position, and [1,2,4]triazole[4,3-a]pyrimidine substituted at the 3 position;   (VI) a 10-membered aryl or heteroaryl group, however; when A is A1 or A1′; C is C1, C1′ or C2; L is L1 or L1′ and L3 is L4 the following species are excluded: an unsubstituted tetrahydroquinoline and 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine substituted at the 3-position;   (VII) (optionally substituted alkyl)-(optionally substituted cycloalkyl), (optionally substituted alkenyl)-(optionally substituted cycloalkyl), or (optionally substituted alkynyl)-(optionally substituted cycloalkyl);       

     wherein B3 can be further substituted one or more times with the substituents independently selected from R 35 , R 36  and R 48 . 
     Non-limiting examples of B3 include the structures of  FIG.  13   . 
     In one embodiment, the methyl groups in the structures illustrated in  FIG.  13    can be replaced by another alkyl group. In another embodiment, the B3 groups illustrated in  FIG.  13    can be optionally substituted. As indicated above, any of the structures illustrated in  FIG.  13    or otherwise herein can be optionally substituted with 0, 1, 2, 3, or 4, as appropriate, and independently, with an R 48  substituent. 
     In an alternative embodiment, B3 can also be R 21  when L2 is either an optionally substituted monocyclic or bicyclic carbocyclic; an optionally substituted monocyclic or bicyclic carbocyclic-oxy group; an optionally substituted monocyclic or bicyclic heterocyclic group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and from 4 to 7 ring atoms per ring, an optionally substituted —(C 0 -C 4 alkyl)(aryl); an optionally substituted —(C 0 -C 4 alkyl)(5-membered heteroaryl) selected from pyrrole, furan, thiophene, pyrazole, oxazole, isoxazole, thiazole and isothiazole or a substituted imidazole; an optionally substituted —(C 0 -C 4 alkyl)(6-membered heteroaryl); an optionally substituted —(C 0 -C 4 alkyl)(8-membered heteroaryl); an optionally substituted —(C 0 -C 4 alkyl)(9-membered heteroaryl) selected from isoindole, indazole, purine, indolizine, benzothiophene, benzothiazole, benzoxazole, benzofuran, and furopyridine; or an optionally substituted —(C 0 -C 4 alkyl)(10-membered heteroaryl) 
     Non-limiting examples of L2-B3 where B3 is R 21  include the structures of  FIG.  14   . 
     B4 is one of the following defined embodiments and is subject to the restriction that either A is A2, or C is C3 (or C4), or L is L2, or L3 is L5:
         (I) a 4-membered carbocyclic fused to a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the 4-5 or 4-6 ring system can be optionally substituted;   (II) a 4-membered carbocyclic fused to a 6-membered aryl ring wherein the 4-6 ring system can be optionally substituted;   (III) a monocyclic or bicyclic carbocyclic; a monocyclic or bicyclic carbocyclic-oxy group; a monocyclic, bicyclic, or tricyclic heterocyclic group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and from 4 to 7 ring atoms per ring; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; —(C 0 -C 4 alkyl)(aryl); (C 0 -C 4 alkyl)(heteroaryl); or —(C 0 -C 4 alkyl)(biphenyl); each of which B3 is substituted one or more times with S(O) 2 OR 21 ;   (IV) (cycloalkyl)-(optionally substituted aryl), (cycloalkyl)-(optionally substituted heteroaryl), (cycloalkyl)-(optionally substituted heterocyclic), (alkyl)-alkenyl), cycloalkyl-alkenyl;   (V) alkyl, (alkyl)-(alkenyl), alkyl(alkynyl), cycloalkyl-alkenyl each of which can be optionally substituted;   (VI) (optionally substituted alkyl)-(optionally substituted cycloalkyl), (alkenyl)-(optionally substituted cycloalkyl), (alkynyl)-(optionally substituted cycloalkyl), (optionally substituted cycloalkyl)-(optionally substituted cycloalkyl);       

     wherein B4 can be further substituted 1, 2, 3 or 4 times or more with the substituents independently selected from R 33 , R 34 , R 35  R 36  and R 48 . 
     In an alternate embodiment, the R 32  group in divalent form can be bonded to B via a linking group to form a compound of Formula I′: 
     
       
         
         
             
             
         
       
     
     wherein; 
     X 9  is CH 2  or O and X 10  is CH 2 , NR 9 , O or S; 
     p is 2 to 10; 
     or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof. 
     In one embodiment, the disclosure provides a compound of Formula IM. 
     
       
         
         
             
             
         
       
     
     In one embodiment, the disclosure provides a compound of Formula IN: 
     
       
         
         
             
             
         
       
     
     In one embodiment, the disclosure provides a compound of Formula IO: 
     
       
         
         
             
             
         
       
     
     In one embodiment, the disclosure provides a compound of Formula IP: 
     
       
         
         
             
             
         
       
     
     In one embodiment, the disclosure provides a compound of Formula IQ: 
     
       
         
         
             
             
         
       
     
     In one embodiment, the disclosure provides a compound of Formula IR: 
     
       
         
         
             
             
         
       
     
     In an alternate embodiment, the X 9 —(CH 2 ) p —X 10  moiety can be saturated or partially unsaturated. In another embodiment, the X 9 —(CH 2 ) p —X 10  moiety can comprise one or more heteroatom s. 
     In an alternate embodiment, the A group can be bonded to B via a linking group to form a compound of Formula I′A: 
     
       
         
         
             
             
         
       
     
     wherein; 
     X 9′  and X 10  are each independently CH 2 , NR 9 , O or S; 
     t is 1, 2, or 3; 
     or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof. 
     In one embodiment, the disclosure provides a compound of Formula IS: 
     
       
         
         
             
             
         
       
     
     In one embodiment, the disclosure provides a compound of Formula IT: 
     
       
         
         
             
             
         
       
     
     In an alternate embodiment, the X 9 —(CH 2 ) t —X 10  moiety can be saturated or partially unsaturated. In another embodiment, the X 9 —(CH 2 ) t —X 10  moiety can comprise one or more heteroatom s. 
     In an alternate embodiment, the disclosure provides compounds of Formula I″ 
                         
or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof.
 
     A is selected from A1, A1′ and A2. 
     Bis selected from B1, B1′, B2, B3, and B4. 
     L is selected from L1, L1′, L2, and L2′. 
     L3 is selected from L4 and L5. 
     R 37  is hydrogen, C 1 -C 6 alkyl or —(C 0 -C 2 alkyl)(C 3 -C 6 cycloalkyl). 
     R 38  and R 39  are independently hydrogen (which as in any other location can be deuterium), C 1 -C 6 alkyl (including C 1 -C 3  alkyl), C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, (C 3 -C 6 cycloalkyl)C 0 -C 4 alkyl-, (aryl)C 0 -C 2 alkyl-, (heteroaryl)C 0 -C 2 alkyl-, or a side chain of an amino acid (i.e., a moiety which is found on the carbon linking the amino group and the carboxyl group in an amino acid) or its isomer; each of which is optionally substituted. The R 38  and R 39  substituents independently include but are not limited to any corresponding R 38  and R 39  positions found in natural amino acids (or their D-counterpart) (i.e., the substituents on the carbon between the carbonyl and the amino group) and non-proteogenic amino acids, such as serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine (e.g., hydrogen), alanine, valine, isoleucine, methionine, phenylalanine, tyrosine, tryptophan, ornithine, glutamine, arginine, histidine, proline, hydroxyproline, selenomethionine, lanthionine, 2-aminoisobutyric acid or dehydroalanine (i.e., R 38  or R 39  is an exo-double bond), with optional protection of functional groups such as hydroxyl, amino, thiol, etc. 
     Pharmaceutical compositions comprising a compound or salt of Formula I, Formula I′ or Formula I″ together with a pharmaceutically acceptable carrier are also disclosed. 
     The present invention thus includes at least the following features:
     (i) a compound of Formula I, Formula I′ or Formula I″ or a pharmaceutically acceptable salt or prodrug thereof, for use in treating or preventing a disorder listed in the Detailed Description, Part V, including but not limited to the development of fatty liver and conditions stemming from fatty liver, such as nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, or liver failure; dermatomyocitis; amyotrophic lateral sclerosis; cytokine or inflammatory reactions in response to biotherapeutics (e.g. CAR T-cell therapy); paroxysmal nocturnal hemoglobinuria (PNH), rheumatoid arthritis, multiple sclerosis, age-related macular degeneration (AMD), retinal degeneration, other ophthalmic diseases (e.g., geographic atrophy), a respiratory disease or a cardiovascular disease;   (ii) a pharmaceutically acceptable composition of a compound of Formula I, Formula I′ or Formula I″ or its pharmaceutically acceptable salt in a pharmaceutically acceptable carrier;   (iii) a compound selected from Formula I, Formula I′ or Formula I″ or a pharmaceutically acceptable salt or prodrug thereof, for use in treating or preventing a disorder mediated by the complement pathway, and for example, cascade Factor D;   (iv) use of a compound of Formula I, Formula I′ or Formula I″, as described herein, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for treating or preventing a disorder listed in the Detailed Description, Part V, including but not limited to the development of fatty liver and conditions stemming from fatty liver, such as nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, liver failure; dermatomyocitis; amyotrophic lateral sclerosis; cytokine or inflammatory reactions in response to biotherapeutics (e.g. CAR T-cell therapy); paroxysmal nocturnal hemoglobinuria (PNH), rheumatoid arthritis, multiple sclerosis, age-related macular degeneration (AMD), retinal degeneration, other ophthalmic diseases (e.g., geographic atrophy), a respiratory disease or a cardiovascular disease;   (v) a process for manufacturing a medicament intended for the therapeutic use for treating or preventing a disorder listed in the Detailed Description, Part V, or generally for treating or preventing disorders mediated by complement cascade Factor D, characterized in that a compound selected from Formula I, Formula I′ or Formula I″ or an embodiment of the active compound is used in the manufacture;   (vi) a compound selected from Formula I, Formula I′ or Formula I″ or a salt thereof as described herein in substantially pure form (e.g., at least 90 or 95%):   (vii) a compound of Formula I, Formula I′ or Formula I″ as described herein, or a pharmaceutically acceptable salt or prodrug thereof, for use in treating a medical disorder which 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 ability of the cell to engage in or respond to normal complement activity, or an undesired complement-mediated response to a medical treatment, such as surgery or other medical procedure or a pharmaceutical or biopharmaceutical drug administration, a blood transfusion, or other allogenic tissue or fluid administration.   (viii) For each of (a) through (g) above, and otherwise herein, each assembly of moieties in the Figures and each active compound made therefrom or its use is considered and deemed specifically and individually disclosed, as such depiction is for convenience of space only and not intended to describe a only a genus or even a subgenus for such indication.   

    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG.  1    provides non-limiting specific embodiments of the Central Core ring, wherein R, R′, and R 3  are defined below. 
         FIGS.  2 A,  2 B,  2 C,  2 D,  2 E,  2 F,  2 G,  2 H,  2 I,  2 J,  2 K,  2 L, and  2 M , provide non-limiting embodiments of C1′; wherein R 3  is as defined herein. 
         FIG.  3    provides non-limiting embodiments of C2. 
         FIGS.  4 A,  4 B,  4 C,  4 D,  4 E,  4 F,  4 G,  4 H,  4 I,  4 J,  4 K,  4 L,  4 M, and  4 N , provide non-limiting embodiments of C3. 
         FIG.  5    provides non-limiting embodiments of central core small mimetics of a beta-turn, beta turn inducers, reverse turn mimetics and foldamer monomers. 
         FIG.  6    provides non-limiting embodiments of A1′, wherein R 32  is defined below. 
         FIGS.  7 A,  7 B,  7 C,  7 D, and  7 E , provide non-limiting embodiments of A2, wherein R 32  is defined below. 
         FIGS.  8 A,  8 B,  8 C, and  8 D , provide non-limiting embodiments of L1′. 
         FIGS.  9 A,  9 B,  9 C,  9 D,  9 E,  9 F,  9 G,  9 H,  9 I, and  9 J , provide non-limiting embodiments of L2. 
         FIGS.  10 A,  10 B,  10 C, and  10 D , provide non-limiting specific embodiments of B1 rings, wherein R 27 , R 28 , and R 29  are defined below. 
         FIG.  11 A,  11 B,  11 C,  11 D , provide non-limiting specific embodiments of B1′ rings, wherein halo is selected from F, Cl, Br, or I. 
         FIG.  12    provides specific embodiments of B2 rings. 
         FIGS.  13 A,  13 B,  13 C,  13 D,  13 E,  13 F,  13 G,  13 H,  13 I,  13 J,  13 K,  13 L,  13 M,  13 N,  13 O,  13 P,  13 Q,  13 R,  13 S,  13 T,  13 U ,  13 V,  13 W,  13 X,  13 Y, and  13 Z, provide specific embodiments of B3 moieties. 
         FIG.  14    provides non-limiting embodiments of L2-B3 wherein B3 is R 21 , and R 21  is defined below. 
         FIG.  15    provides non-limiting embodiments of R 32 . 
         FIGS.  16 A,  16 B,  16 C,  16 D,  16 E,  16 F,  16 G,  16 H,  16 I,  16 J,  16 K,  16 L,  16 M, and  16 N  provide non-limiting examples of compounds included in the present invention, wherein Z 32  is the same as R 32  as used herein. 
     
    
    
     DETAILED DESCRIPTION 
     I. Terminology 
     Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. 
     The 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 is specifically described, unless otherwise indicated or otherwise clear from the context. 
     The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term “or” means “and/or”. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. 
     The present invention includes compounds of Formula I, Formula I′ or Formula I″ with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as  2 H,  3 H,  11 C,  13 C,  14 C,  15 N,  18 F,  31 P,  32 P,  35 S,  36 C,  36 Cl,  125 I respectively. In one embodiment, isotopically labelled compounds can be used in metabolic studies (with  14 C), reaction kinetic studies (with, for example  2 H or  3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an  18F  labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. 
     By way of general example and without limitation, isotopes of hydrogen, for example, deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in described structures that achieves the desired result. Alternatively or in addition, isotopes of carbon, e.g.,  13 C and  14 C, may be used. In one embodiment, the isotopic substitution is deuterium for hydrogen at one or more locations on the molecule to improve the performance of the drug, for example, the pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, the deuterium can be bound to carbon in a location of bond breakage during metabolism (an α-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a β-deuterium kinetic isotope effect). 
     Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In one embodiments deuterium is 90, 95 or 99% enriched at a desired location. Unless otherwise stated, the enrichment at any point is above natural abundance and enough to alter a detectable property of the drug in a human. 
     In one embodiment, the substitution of a hydrogen atom for a deuterium atom can be provided 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 substitution of a hydrogen atom for a deuterium atom occurs within an R group selected from any of R, R′, R 1 , R 1′ , R 2 , R 2′ , R 3 , R 3′ , R 4 , R 5 , R 6 , R 6′ , R 7 , R 8 , R 8′ , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 19 , R 21 , R 22 , R 23 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 71 , R 101 , or R 102 . For example, when any of R groups are, or contain for example through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in nonlimiting 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 certain other embodiments, when two substituents of the central core ring are combined to form a cyclopropyl ring, the unsubstituted methylene carbon may be deuterated. 
     The compound of the present invention may 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 a salt thereof) with one or more solvent molecules. Nonlimiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents. The term “hydrate” refers to a molecular complex comprising a compound of the invention and water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 -DMSO. A solvate can be in a liquid or solid form. 
     A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —(C═O)NH 2  is attached through carbon of the keto (C═O) group. 
     The term “substituted”, as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a moiety selected from the indicated group, provided that the designated atom&#39;s normal valence is not exceeded and the resulting compound is stable. For example, when the substituent is oxo (i.e., ═O) then two hydrogens on the atom are replaced. For example a pyridyl group substituted by oxo is a pyridone. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. 
     A stable active compound refers to a compound that can be isolated and can be formulated into a dosage form with a shelf life of at least one month. A stable manufacturing intermediate or precursor to an active compound is stable if it does not degrade within the period needed for reaction or other use. A stable moiety or substituent group is one that does not degrade, react or fall apart within the period necessary for use. Nonlimiting examples of unstable moieties are those that combine heteroatoms in an unstable arrangement, as typically known and identifiable to those of skill in the art. 
     Any suitable group may be present on a “substituted” or “optionally substituted” position that forms a stable molecule and meets the desired purpose of the invention and includes, but is not limited to, e.g., halogen (which can 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; alkylthio including those having one or more thioether linkages; alkylsulfinyl; alkylsulfonyl groups including those having one or more sulfonyl linkages; aminoalkyl groups including groups having one or more N atoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like, each ring either substituted or unsubstituted aromatic); arylalkyl having for example, 1 to 3 separate or fused rings and from 6 to about 14 or 18 ring carbon atoms, with benzyl being an exemplary arylalkyl group; arylalkoxy, for example, having 1 to 3 separate or fused rings with benzyloxy being an exemplary arylalkoxy group; or a saturated, unsaturated, or aromatic heterocyclic group having 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, piperazinyl, and pyrrolidinyl. Such heterocyclic groups may be further substituted, e.g. with hydroxy, alkyl, alkoxy, halogen and amino. In certain embodiments “optionally substituted” includes one or more substituents independently selected from halogen, hydroxyl, amino, cyano, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C 1 -C 6 alkoxy, C 2 -C 6 alkanoyl, C 1 -C 6 alkylester, (mono- and di-C 1 -C 6 alkylamino)C 0 -C 2 alkyl, C 1 -C 2 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 C 1 -C 2 haloalkoxy. 
     “Alkyl” is a branched or straight chain saturated aliphatic hydrocarbon group. 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, the alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5  or C 1 -C 6 . The specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species. For example, the term C 1 -C 6  alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species. For example, the term C 1 -C 4 alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. When C 0 -C n  alkyl is used herein in conjunction 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 indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (C 0 alkyl), or attached by an alkyl chain in this case 1, 2, 3, or 4 carbon atoms. Alkyls can also be attached via other groups such as heteroatoms 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, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, and hexyl. In one embodiment, the alkyl group is optionally substituted as described above. In one embodiment, trimethylsilyl can be used instead of t-butyl. 
     In one embodiment, when a term is used that includes “alk” it should be understood that “cycloalkyl” or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context. For example and without limitation, the terms alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkenloxy, haloalkyl, aminoalkyl, alkylene, alkenylene, alkynylene, etc. can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context. 
     “Alkenyl” is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at a stable point along the chain. Nonlimiting 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 specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkenyl include, but are not limited to, ethenyl and propenyl. In one embodiment, the alkenyl group is optionally substituted as described above. 
     “Alkynyl” is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain, for example, C 2 -C 8 alkynyl or C 2 -C 6 alkynyl. The specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. In one embodiment, the alkynyl group is optionally substituted as described above. 
     “Alkylene” is a bivalent saturated hydrocarbon. Alkylenes, for example, can be a 1, 2, 3, 4, 5, 6, 7 to 8 carbon moiety, 1 to 6 carbon moiety, or an indicated 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 bivalent hydrocarbon having at least one carbon-carbon double bond. Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6 carbon moiety, or an indicated number of carbon atoms, for example C 2 -C 4 alkenylene. 
     “Alkynylene” is a bivalent hydrocarbon having at least one carbon-carbon triple bond. Alkynylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6 carbon moiety, or an indicated number of carbon atoms, for example C 2 -C 4 alkynylene. 
     “Alkoxy” is an alkyl group as defined above covalently bound through an oxygen bridge (—O—). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, 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 a “thioalkyl” group is an alkyl group as defined above with the indicated number of carbon atoms covalently bound through a sulfur bridge (—S—). In one embodiment, the alkoxy group is optionally substituted as described above. 
     “Alkenyloxy” is an alkenyl group as defined covalently bound to the group it substitutes by an oxygen bridge (—O—). 
     “Alkanoyl” is an alkyl group as defined above covalently bound through a carbonyl (C═O) bridge. The carbonyl carbon is included in the number of carbons, that is C 2 alkanoyl is a CH 3 (C═O)— group. In one embodiment, the alkanoyl group is optionally substituted as described above. 
     “Alkylester” is an alkyl group as defined herein covalently bound through an ester linkage. The ester linkage may be in either orientation, e.g., a group of the formula —O(C═O)alkyl or a group of the formula —(C═O)Oalkyl. 
     “Amide” or “carboxamide” is —C(O)NR a R b  wherein R a  and R b  are each independently selected from hydrogen, alkyl, for example, C 1 -C 6 alkyl, alkenyl, for example, 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 to which they are bonded, R a  and R b  can form a C 3 -C 7 heterocyclic ring. In one embodiment, the R a  and R b  groups are each independently optionally substituted as described herein. 
     “Carbocyclic group”, “carbocyclic ring”, or “cycloalkyl” is a saturated or partially unsaturated (i.e., not aromatic) group containing all carbon ring atoms. A carbocyclic group typically contains 1 ring of 3 to 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 can have a cycloalkyl group, which 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, the cycloalkyl is a partially unsaturated (i.e., not aromatic) group containing all carbon ring atoms. In another embodiment, the cycloalkyl is a saturated group containing all carbon ring atoms. 
     “Carbocyclic-oxy group” is a monocyclic carbocyclic ring or a mono- or bi-cyclic carbocyclic group as defined above attached to the group it substitutes via an oxygen, —O—, linker. 
     “Haloalkyl” indicates both branched and straight-chain alkyl groups substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl. 
     “Haloalkoxy” indicates a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an 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” indicates independently, any of fluoro, chloro, bromo or iodo. 
     “Aryl” indicates an aromatic group containing only carbon in the aromatic ring or rings. In one embodiment, the aryl group contains 1 to 3 separate or fused rings and is 6 to about 14 or 18 ring atoms, without heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion to a 5 to 7-membered saturated cyclic group that optionally contains 1 or 2 heteroatoms independently selected from N, O, and S, to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment, aryl groups are pendant. An example of a pendant 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 a partially unsaturated (i.e., having one or more double and/or triple bonds within the ring without aromaticity) carbocyclic moiety of 3 to about 12, and more typically 3, 4, 5, 6, 7, 8 to 10 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, the remaining ring atoms being C, where one or more ring atoms is optionally substituted independently with one or more substituents described above. A heterocycle may be a monocycle having 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 having 6 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, S, Si and B), for example: a 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), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley &amp; 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, thietanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, pyrazolidinylimidazolinyl, imidazolidinyl, 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-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl, quinolizinyl, N-pyridyl ureas, and pyrrolopyrimidine. Spiro moieties are also included within the scope of this definition. Examples of a heterocyclic group wherein 1 or 2 ring carbon atoms are substituted with oxo (═O) moieties are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocycle groups herein are optionally substituted independently with one or more substituents described herein, for example, 1, 2 or 3 substituents. 
     “Heterocyclicoxy group” is a monocyclic heterocyclic ring or a bicyclic heterocyclic group as described previously linked to the group it substitutes via an oxygen, —O—, linker. 
     “Heteroaryl” refers to a stable monocyclic aromatic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms selected from N, O, S, and B with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5, 6 or 7 membered aromatic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms selected from N, O, S, and B with 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 or boron. Monocyclic heteroaryl groups typically have from 5, 6 or 7 ring atoms. In some embodiments bicyclic heteroaryl groups are 9- to 10-membered heteroaryl groups, that is, groups containing 9 or 10 ring atoms in which one 5, 6 or 7 member aromatic ring is fused to a second aromatic or non-aromatic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. 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, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, tetrahydrofuranyl, and furopyridinyl. Heteroaryl groups are optionally substituted independently with one or more substituents described herein. “Heteroaryloxy” is a heteroaryl group as described bound to the group it substituted via an oxygen, —O—, linker. 
     “Heterocycloalkyl” is a saturated ring group. It may have, for example, 1, 2, 3, or 4 heteroatoms independently selected from N, S, O, Si and B with remaining ring atoms being carbon. In a typical embodiment, nitrogen is the heteroatom. Monocyclic heterocycloalkyl groups typically have from 3 to about 8 ring atoms or from 4 to 6 ring atoms. Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl, and pyrrolinyl. 
     The term “mono- and/or di-alkylamino” indicate a secondary or tertiary alkylamino group, wherein the alkyl groups are independently selected alkyl groups, as defined herein. The point of attachment of the alkylamino group is on the nitrogen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino. 
     A “dosage form” means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like. A “dosage form” can also include an implant, for example an optical implant. 
     “Pharmaceutical compositions” are compositions comprising 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 which 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 the disclosed compound in which the parent compound is modified by making inorganic and organic, pharmaceutically acceptable, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts. 
     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 acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC—(CH 2 ) n —COOH where n is 0-4, and the like, or using a different acid that produces the same counterion. Lists of additional suitable salts may be found, e.g., in  Remington&#39;s Pharmaceutical Sciences,  17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985). 
     The term “carrier” applied to pharmaceutical compositions/combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided. 
     A “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition/combination that is generally safe, non-toxic and neither biologically nor otherwise inappropriate for administration to a host, typically 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 by modulation of the complement Factor D pathway. Typically the host is a human. A “patient” or “host” or “subject” also refers to for example, a mammal, primate (e.g., human), cows, sheep, goat, horse, dog, cat, rabbit, rat, mice, fish, bird and the like. 
     A “prodrug” as used herein, means a compound which when administered to a host in vivo is converted into a parent drug. As used herein, the term “parent drug” means any of the presently described chemical compounds described herein. Prodrugs can be used to achieve any desired effect, including to enhance properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent. Prodrug strategies exist which provide choices in modulating the conditions for in vivo generation of the parent drug, all of which are deemed included herein. Nonlimiting examples of prodrug strategies include covalent attachment of removable groups, or removable portions of groups, for example, but not limited to acylation, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation or anhydride, among others. 
     “Providing a compound with at least one additional active agent,” for example, in one embodiment can mean that the compound and the additional active agent(s) are provided simultaneously in a single dosage form, provided concomitantly in separate dosage forms, or provided in separate dosage forms for administration. In one embodiment, the compound administrations are separated by some amount of time that is within the time in which both the compound and the at least one additional active agent are within the blood stream of a patient. In certain embodiments the compound and the additional active agent need not be prescribed for a patient by the same medical care worker. In certain embodiments the additional active agent or agents need not require a prescription. Administration of the compound or the at least one additional active agent can occur via any appropriate route, for example, oral tablets, oral capsules, oral liquids, inhalation, injection, suppositories, parenteral, sublingual, buccal, intravenous, intraaortal, transdermal, polymeric controlled delivery, non-polymeric controlled delivery, nano or microparticles, liposomes, and/or topical contact. 
     A “therapeutically effective amount” of a pharmaceutical composition/combination of this invention means an amount effective, when administered to a host, to provide a therapeutic benefit such as an amelioration of symptoms or reduction or dimunition of the disease itself. In one embodiment, a therapeutically effective amount is an amount sufficient to prevent a significant increase or will significantly reduce the detectable level of complement Factor D in the patient&#39;s blood, serum, or tissues. 
     II. Detailed Description of the Active Compounds 
     According to the present invention, a compound of Formula I is provided: 
                         
as well as the pharmaceutically acceptable salts and compositions thereof. Formula I can be considered to have a central core C, an L substituent, a B substituent, and a L3-A substituent. Formula I comprises at least one of the A2, B3, C3, L2, L2′, or L5 (and in certain embodiments, C4) moieties described herein. The invention includes a compound of Formula I, or a pharmaceutically acceptable salt or composition thereof, wherein R 12  or R 13  on the A group is an amide substituent, for example an R 32 . In one embodiment, the compound is an inhibitor of complement factor D, and therefore can be used as an effective amount to treat a host in need of complement factor D modulation. In another embodiment, the compound acts through a mechanism other than inhibition of complement D to treat a disorder described herein in a host, typically a human.
 
     The present invention also includes a compound of Formula I′: 
                         
as well as the pharmaceutically acceptable salts and compositions thereof. Formula I′ has a central core C moiety, an A substituent, a L3 substituent, a L substituent, a B substituent and a —X 9 —(CH 2 ) p —X 10  linker; wherein R 12  or R 13  on the A1 or A2 group is an amide substituent, for example an R 32 . In one embodiment, this compound is an inhibitor of complement factor D, and therefore can be used as an effective amount to treat a host in need of complement factor D modulation. Alternatively, the compound may act through a different mechanism of action to treat the disorders described herein.
 
     In addition, the present invention provides a compound of Formula I″: 
                         
as well as the pharmaceutically acceptable salts and compositions thereof. Formula I″ has an
 
                         
moiety, an A substituent, a L3 substituent, a L substituent and a B substituent. Compounds of Formula I″, or a pharmaceutically acceptable salt or composition thereof, wherein R 12  or R 13  on the A1 or A2 group is an amide substituent, for example an R 32 . In one embodiment, this compound is an inhibitor of complement factor D, and therefore can be used as an effective amount to treat a host in need of complement factor D modulation. Alternatively, the compound may act through a different mechanism of action to treat the disorders described herein.
 
     Non-limiting examples of compounds falling within Formula I and Formula I′ with variations in the variables e.g., A, B, R 1 -R 3′ , and L, are described below. 
     Non-limiting examples of compounds falling within Formula r′ with variations in the variables e.g., R 37 , R 38 , R 39 , A, B, L and L3 are described below. The disclosure includes all combinations of these definitions as long as a stable compound results. 
     In certain embodiments, any of the active compounds can be provided in its N-oxide form to a patient in need thereof. In a different embodiment, an N-oxide of one of the active compounds or a precursor of the active compound is used in a manufacturing scheme. In yet another embodiment, the N-oxide is a metabolite of administration of one of the active compounds herein, and may have independent activity. The N-oxide can be formed by treating the compound of interest with an oxidizing agent, for example a suitable peroxyacid or peroxide, to generate an N-oxide compound. For example, a heteroaryl group, for example 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 generate an N-oxide compound, A person skilled in the art will understand that appropriate protecting groups may be necessary to carry out the chemistry. See, Jain, S. L. et al., “Rhenium-Catalyzed Highly Efficient Oxidations of Tertiary Nitrogen Compounds to N-Oxides Using Sodium Percarbonate as Oxygen Source, Synlett, 2261-2663, 2006. 
     In other embodiments, any of the active compounds with a sulfur can be provided in its sulfoxide or sulfone form to a patient in need thereof. In a different embodiment, a sulfoxide or sulfone of one of the active compounds or a precursor of the active compound is used in a manufacturing scheme. A sulfur atom in a selected compound as described herein can be oxidized to form a sulfoxide 
                         
or a sulfone
 
                         
using known methods. For example, the compound 1,3,5-triazo-2,4,6-triphosphorine-2,2,4,4,6,6-tetrachloride (TAPC) is an efficient promoter for the oxidation of sulfides to sulfoxides. See, Bahrami, M. et al., “TAPC-Promoted Oxidation of sulfides and Deoxygenation of Sulfoxides”, J. Org. Chem., 75, 6208-6213 (2010). Oxidation of sulfides with 30% hydrogen peroxide catalyzed by tantalum carbide provides 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, for example, niobium carbide as the 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). Urea-hydrogen peroxide adduct is a stable inexpensive and easily handled reagent for the oxidation of sulfides to sulfones, see Varma, R. S. and Naicker, K. P., “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 other heteroatoms, such as nitrogen, may need to be protected and then deprotected while carrying out the oxidation of a sulfur atom to produce the desired compound.
 
Formulas 2 Through 654
 
     In one aspect, the disclosure includes compounds and salts of Formulas 2-654 for any use and in any composition described in this application. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Exemplary Compounds within the Present Invention. 
               
            
           
           
               
               
               
               
            
               
                 Formula 
                   
                 Formula 
                   
               
               
                 No. 
                 Formula 
                 No. 
                 Formula 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 2 
                 A1L4C1L1B3 
                 300 
                 A1′L5C1′L1′B2 
               
               
                 3 
                 A1L4C1L1′B3 
                 301 
                 A1′L5C1′L1′B3 
               
               
                 4 
                 A1L4C1L2B1 
                 302 
                 A1′L5C1′L2B1 
               
               
                 5 
                 A1L4C1L2B1′ 
                 303 
                 A1′L5C1′L2B1′ 
               
               
                 6 
                 A1L4C1L2B2 
                 304 
                 A1′L5C1I2B2 
               
               
                 7 
                 A1L4C1L2B3 
                 305 
                 A1′L5C1′L2B3 
               
               
                 8 
                 A1L4C1′L1B3 
                 306 
                 A1′L5C2L1B1 
               
               
                 9 
                 A1L4C1′L1′B3 
                 307 
                 A1′L5C2L1B1′ 
               
               
                 10 
                 A1L4C1′L2B1 
                 308 
                 A1′L5C2L1B2 
               
               
                 11 
                 A1L4C1′L2B1′ 
                 309 
                 A1′L5C2L1B3 
               
               
                 12 
                 A1L4C1L2B2 
                 310 
                 A1′L5C2L1′B1 
               
               
                 13 
                 A1L4C1L2B3 
                 311 
                 A1′L5C2L1′B1′ 
               
               
                 14 
                 A1L4C2L1B3 
                 312 
                 A1′L5C2L1′B2 
               
               
                 15 
                 A1L4C2L1′B3 
                 313 
                 A1′L5C2L1′B3 
               
               
                 16 
                 A1L4C2L2B1 
                 314 
                 A1′L5C2L2B1 
               
               
                 17 
                 A1L4C2L2B1′ 
                 315 
                 A1′L5C2L2B1′ 
               
               
                 18 
                 A1L4C2L2B2 
                 316 
                 A1′L5C2L2B2 
               
               
                 19 
                 A1L4C2L2B3 
                 317 
                 A1′L5C2L2B3 
               
               
                 20 
                 A1L4C3L1B1 
                 318 
                 A1′L5C3L1B1 
               
               
                 21 
                 A1L4C3L1B1′ 
                 319 
                 A1′L5C3L1B1′ 
               
               
                 22 
                 A1L4C3L1B2 
                 320 
                 A1′L5C3L1B2 
               
               
                 23 
                 A1L4C3L1B3 
                 321 
                 A1′L5C3L1B3 
               
               
                 24 
                 A1L4C3L1′B1 
                 322 
                 A1′L5C3L1′B1 
               
               
                 25 
                 A1L4C3L1′B1′ 
                 323 
                 A1′L5C3L1′B1′ 
               
               
                 26 
                 A1L4C3L1′B2 
                 324 
                 A1′L5C3L1′B2 
               
               
                 27 
                 A1L4C3L1′B3 
                 325 
                 A1′L5C3L1′B3 
               
               
                 28 
                 A1L4C3L2B1 
                 326 
                 A1′L5C3L2B1 
               
               
                 29 
                 A1L4C3L2B1′ 
                 327 
                 A1′L5C3L2B1′ 
               
               
                 30 
                 A1L4C3L2B2 
                 328 
                 A1′L5C3L2B2 
               
               
                 31 
                 A1L4C3L2B3 
                 329 
                 A1′L5C3L2B3 
               
               
                 32 
                 A1L5C1L1B1 
                 330 
                 A2L4C1L1B1 
               
               
                 33 
                 A1L5C1L1B1′ 
                 331 
                 A2L4C1L1B1′ 
               
               
                 34 
                 A1L5C1L1B2 
                 332 
                 A2L4C1L1B2 
               
               
                 35 
                 A1L5C1L1B3 
                 333 
                 A2L4C1L1B3 
               
               
                 36 
                 A1L5C1L1′B1 
                 334 
                 A2L4C1L1′B1 
               
               
                 37 
                 A1L5C1L1′B1′ 
                 335 
                 A2L4C1L1′B1′ 
               
               
                 38 
                 A1L5C1L1′B2 
                 336 
                 A2L4C1L1′B2 
               
               
                 39 
                 A1L5C1L1′B3 
                 337 
                 A2L4C1L1′B3 
               
               
                 40 
                 A1L5C1L2B1 
                 338 
                 A2L4C1L2B1 
               
               
                 41 
                 A1L5C1L2B1′ 
                 339 
                 A2L4C1L2B1′ 
               
               
                 42 
                 A1L5C1L2B2 
                 340 
                 A2L4C1L2B2 
               
               
                 43 
                 A1L5C1L2B3 
                 341 
                 A2L4C1L2B3 
               
               
                 44 
                 A1L5C1′L1B1 
                 342 
                 A2L4C1′L1B1 
               
               
                 45 
                 A1L5C1′L1B1′ 
                 343 
                 A2L4C1′L1B1′ 
               
               
                 46 
                 A1L5C1′L1B2 
                 344 
                 A2L4C1I1B2 
               
               
                 47 
                 A1L5C1′L1B3 
                 345 
                 A2L4C1′L1B3 
               
               
                 48 
                 A1L5C1′L1′B1 
                 346 
                 A2L4C1′L1′B1 
               
               
                 49 
                 A1L5C1′L1′B1′ 
                 347 
                 A2L4C1′L1′B1′ 
               
               
                 50 
                 A1L5C′L1′B2 
                 348 
                 A2L4C1′L1′B2 
               
               
                 51 
                 A1L5C′L1′B3 
                 349 
                 A2L4C1′L1′B3 
               
               
                 52 
                 A1L5C1′L2B1 
                 350 
                 A2L4C1′L2B1 
               
               
                 53 
                 A1L5C1′L2B1′ 
                 351 
                 A2L4C1′L2B1′ 
               
               
                 54 
                 A1L5C1′L2B2 
                 352 
                 A2L4C1′L2B2 
               
               
                 55 
                 A1L5C1′L2B3 
                 353 
                 A2L4C1′L2B3 
               
               
                 56 
                 A1L5C2L1B1 
                 354 
                 A2L4C2L1B1 
               
               
                 57 
                 A1L5C2L1B1′ 
                 355 
                 A2L4C2L1B1′ 
               
               
                 58 
                 A1L5C2L1B2 
                 356 
                 A2L4C2L1B2 
               
               
                 59 
                 A1L5C2L1B3 
                 357 
                 A2L4C2L1B3 
               
               
                 60 
                 A1L5C2L1′B1 
                 358 
                 A2L4C2L1′B1 
               
               
                 61 
                 A1L5C2L1′B1′ 
                 359 
                 A2L4C2L1′B1′ 
               
               
                 62 
                 A1L5C2L1′B2 
                 360 
                 A2L4C2L1′B2 
               
               
                 63 
                 A1L5C2L1′B3 
                 361 
                 A2L4C2L1′B3 
               
               
                 64 
                 A1L5C2L2B1 
                 362 
                 A2L4C2L2B1 
               
               
                 65 
                 A1L5C2L2B1′ 
                 363 
                 A2L4C2L2B1′ 
               
               
                 66 
                 A1L5C2L2B2 
                 364 
                 A2L4C2L2B2 
               
               
                 67 
                 A1L5C2L2B3 
                 365 
                 A2L4C2L2B3 
               
               
                 68 
                 A1L5C3L1B1 
                 366 
                 A2L4C3L1B1 
               
               
                 69 
                 A1L5C3L1B1′ 
                 367 
                 A2L4C3L1B1′ 
               
               
                 70 
                 A1L5C3L1B2 
                 368 
                 A2L4C3L1B2 
               
               
                 71 
                 A1L5C3L1B3 
                 369 
                 A2L4C3L1B3 
               
               
                 72 
                 A1L5C3L1′B1 
                 370 
                 A2L4C3L1′B1 
               
               
                 73 
                 A1L5C3L1′B1′ 
                 371 
                 A2L4C3L1′B1′ 
               
               
                 74 
                 A1L5C3L1′B2 
                 372 
                 A2L4C3L1′B2 
               
               
                 75 
                 A1L5C3L1′B3 
                 373 
                 A2L4C3L1′B3 
               
               
                 76 
                 A1L5C3L2B1 
                 374 
                 A2L4C3L2B1 
               
               
                 77 
                 A1L5C3L2B1′ 
                 375 
                 A2L4C3L2B1′ 
               
               
                 78 
                 A1L5C3L2B2 
                 376 
                 A2L4C3L2B2 
               
               
                 79 
                 A1L5C3L2B3 
                 377 
                 A2L4C3L2B3 
               
               
                 80 
                 A1′L4C1L1B3 
                 378 
                 A2L5C1L1B1 
               
               
                 81 
                 A1′L4C1L1′B3 
                 379 
                 A2L5C1L1B1′ 
               
               
                 82 
                 A1′L4C1L2B1 
                 380 
                 A2L5C1L1B2 
               
               
                 83 
                 A1′L4C1L2B1′ 
                 381 
                 A2L5C1L1B3 
               
               
                 84 
                 A1′L4C1L2B2 
                 382 
                 A2L5C1L1′B1 
               
               
                 85 
                 A1′L4C1L2B3 
                 383 
                 A2L5C1L1′B1′ 
               
               
                 86 
                 A1′L4C1′L1B3 
                 384 
                 A2L5C1L1′B2 
               
               
                 87 
                 A1′L4C1′L1′B3 
                 385 
                 A2L5C1L1′B3 
               
               
                 88 
                 A1L4C1′L2B1 
                 386 
                 A2L5C1L2B1 
               
               
                 89 
                 A1′L4C1′L2B1′ 
                 387 
                 A2L5C1L2B1′ 
               
               
                 90 
                 A1L4C1′L2B2 
                 388 
                 A2L5C1L2B2 
               
               
                 91 
                 A1L4C1′L2B3 
                 389 
                 A2L5C1L2B3 
               
               
                 92 
                 A1′L4C2L1B3 
                 390 
                 A2L5C1′L1B1 
               
               
                 93 
                 A1′L4C2L1′B3 
                 391 
                 A2L5C1′L1B1′ 
               
               
                 94 
                 A1′L4C2L2B1 
                 392 
                 A2L5C1′L1B2 
               
               
                 95 
                 A1′L4C2L2B1′ 
                 393 
                 A2L5C1′L1B3 
               
               
                 96 
                 A1′L4C2L2B2 
                 394 
                 A2L5C1′L1′B1 
               
               
                 97 
                 A1′L4C2L2B3 
                 395 
                 A2L5C1′L1′B1′ 
               
               
                 98 
                 A1′L4C3L1B1 
                 396 
                 A2L5C1′L1′B2 
               
               
                 99 
                 A1′L4C3L1B1′ 
                 397 
                 A2L5C1′L1′B3 
               
               
                 100 
                 A1′L4C3L1B2 
                 398 
                 A2L5C1′L2B1 
               
               
                 101 
                 A1′L4C3L1B3 
                 399 
                 A2L5C1′L2B1′ 
               
               
                 102 
                 A1′L4C3L1′B1 
                 400 
                 A2L5C1′L2B2 
               
               
                 103 
                 A1′L4C3L1′B1′ 
                 401 
                 A2L5C1′L2B3 
               
               
                 104 
                 A1′L4C3L1′B2 
                 402 
                 A2L5C2L1B1 
               
               
                 105 
                 A1′L4C3L1′B3 
                 403 
                 A2L5C2L1B1′ 
               
               
                 106 
                 A1′L4C3L2B1 
                 404 
                 A2L5C2L1B2 
               
               
                 107 
                 A1′L4C3L2B1′ 
                 405 
                 A2L5C2L1B3 
               
               
                 108 
                 A1′L4C3L2B2 
                 406 
                 A2L5C2L1′B1 
               
               
                 109 
                 A1′L4C3L2B3 
                 407 
                 A2L5C2L1′B1′ 
               
               
                 110 
                 A1′L5C1L1B1 
                 408 
                 A2L5C2L1′B2 
               
               
                 111 
                 A1′L5C1L1B1′ 
                 409 
                 A2L5C2L1′B3 
               
               
                 112 
                 A1′L5C1L1B2 
                 410 
                 A2L5C2L2B1 
               
               
                 113 
                 A1′L5C1L1B3 
                 411 
                 A2L5C2L2B1′ 
               
               
                 114 
                 A1′L5C1L1′B1 
                 412 
                 A2L5C2L2B2 
               
               
                 115 
                 A1′L5C1L1′B1′ 
                 413 
                 A2L5C2L2B3 
               
               
                 116 
                 A1′L5C1L1′B2 
                 414 
                 A2L5C3L1B1 
               
               
                 117 
                 A1′L5C1L1′B3 
                 415 
                 A2L5C3L1B1′ 
               
               
                 118 
                 A1′L5C1L2B1 
                 416 
                 A2L5C3L1B2 
               
               
                 119 
                 A1′L5C1L2B1′ 
                 417 
                 A2L5C3L1B3 
               
               
                 120 
                 A1′L5C1L2B2 
                 418 
                 A2L5C3L1′B1 
               
               
                 121 
                 A1′L5C1L2B3 
                 419 
                 A2L5C3L1′B1′ 
               
               
                 122 
                 A1′L5CFL1B1 
                 420 
                 A2L5C3L1′B2 
               
               
                 123 
                 A1′L5CFL1B1′ 
                 421 
                 A2L5C3L1′B3 
               
               
                 124 
                 A1′L5C1′L1B2 
                 422 
                 A2L5C3L2B1 
               
               
                 125 
                 A1′L5C1′L1B3 
                 423 
                 A2L5C3L2B1′ 
               
               
                 126 
                 A1′L5C1′L1′B1 
                 424 
                 A2L5C3L2B2 
               
               
                 127 
                 A1′L5C1′L1′B1′ 
                 425 
                 A2L5C3L2B3 
               
               
                 128 
                 A2L4C1L1B4 
                 426 
                 A1′L4C3L1B4 
               
               
                 129 
                 A2L4C1L1′B4 
                 427 
                 A1′L4C3L1′B4 
               
               
                 130 
                 A2L4C1L2B4 
                 428 
                 A1′L4C3L2B4 
               
               
                 131 
                 A2L4C1I1B4 
                 429 
                 A1′L5C3L1B4 
               
               
                 132 
                 A2L4C1′L1′B4 
                 430 
                 A1′L5C3L1′B4 
               
               
                 133 
                 A2L4C1′L2B4 
                 431 
                 A1′L5C3L2B4 
               
               
                 134 
                 A2L4C2L1B4 
                 432 
                 A1L4C1L2B4 
               
               
                 135 
                 A2L4C2L1′B4 
                 433 
                 A1L4C1I2B4 
               
               
                 136 
                 A2L4C2L2B4 
                 434 
                 A1L4C2L2B4 
               
               
                 137 
                 A2L4C3L1B4 
                 435 
                 A1L5C1L2B4 
               
               
                 138 
                 A2L4C3L1′B4 
                 436 
                 A1L5C1′L2B4 
               
               
                 139 
                 A2L4C3L2B4 
                 437 
                 A1L5C2L2B4 
               
               
                 140 
                 A2L5C1L1B4 
                 438 
                 A1′L4C1L2B4 
               
               
                 141 
                 A2L5C1L1′B4 
                 439 
                 A1′L4C1I2B4 
               
               
                 142 
                 A2L5C1L2B4 
                 440 
                 A1′L4C2L2B4 
               
               
                 143 
                 A2L5C1′L1B4 
                 441 
                 A1′L5C1L2B4 
               
               
                 144 
                 A2L5C1′L1′B4 
                 442 
                 A1′L5C1I2B4 
               
               
                 145 
                 A2L5C1′L2B4 
                 443 
                 A1′L5C2L2B4 
               
               
                 146 
                 A2L5C2L1B4 
                 444 
                 A1L5C1L1B4 
               
               
                 147 
                 A2L5C2L1′B4 
                 445 
                 A1L5C1L1′B4 
               
               
                 148 
                 A2L5C2L2B4 
                 446 
                 A1L5C1′L1B4 
               
               
                 149 
                 A2L5C3L1B4 
                 447 
                 A1L5C1′L1′B4 
               
               
                 150 
                 A2L5C3L1′B4 
                 448 
                 A1L5C2L1B4 
               
               
                 151 
                 A2L5C3L2B4 
                 449 
                 A1L5C2L1′B4 
               
               
                 152 
                 A1L4C3L1B4 
                 450 
                 A1′L5C1L1B4 
               
               
                 153 
                 A1L4C3L1′B4 
                 451 
                 A1′L5C1L1′B4 
               
               
                 154 
                 A1L4C3L2B4 
                 452 
                 A1′L5C1′L1B4 
               
               
                 155 
                 A1L5C3L1B4 
                 453 
                 A1′L5C1′L1′B4 
               
               
                 156 
                 A1L5C3L1′B4 
                 454 
                 A1′L5C2L1B4 
               
               
                 157 
                 A1L5C3L2B4 
                 455 
                 A1′L5C2L1′B4 
               
               
                 158 
                 A1L4C4L2B1 
                 456 
                 A1′L5C4L2B1 
               
               
                 159 
                 A1L4C4L2B1′ 
                 457 
                 A1′L5C4L2B1′ 
               
               
                 160 
                 A1L4C4L2B2 
                 458 
                 A1′L5C4L2B2 
               
               
                 161 
                 A1L4C4L2B3 
                 459 
                 A1′L5C4L2B3 
               
               
                 162 
                 A1L5C4L2B1 
                 460 
                 A2L4C4L2B1 
               
               
                 163 
                 A1L5C4L2B1′ 
                 461 
                 A2L4C4L2B1′ 
               
               
                 164 
                 A1L5C4L2B2 
                 462 
                 A2L4C4L2B2 
               
               
                 165 
                 A1L5C4L2B3 
                 463 
                 A2L4C4L2B3 
               
               
                 166 
                 A1′L4C4L2B1 
                 464 
                 A2L5C4L2B1 
               
               
                 167 
                 A1′L4C4L2B1′ 
                 465 
                 A2L5C4L2B1′ 
               
               
                 168 
                 A1′L4C4L2B2 
                 466 
                 A2L5C4L2B2 
               
               
                 169 
                 A1′L4C4L2B3 
                 467 
                 A2L5C4L2B3 
               
               
                 170 
                 A2L4C4L2B4 
                 468 
                 A1′L4C4L2B4 
               
               
                 171 
                 A2L5C4L2B4 
                 469 
                 A1′L5C4L2B4 
               
               
                 172 
                 A1L4C4L2B4 
                 470 
                 A1′L5C4L2′B1 
               
               
                 173 
                 A1L5C4L2B4 
                 471 
                 A1′L5C4L2′B1′ 
               
               
                 174 
                 A1L4C4L2′B1 
                 472 
                 A1′L5C4L2′B2 
               
               
                 175 
                 A1L4C4L2′B1′ 
                 473 
                 A1′L5C4L2′B3 
               
               
                 176 
                 A1L4C4L2′B2 
                 474 
                 A2L4C4L2′B1 
               
               
                 177 
                 A1L4C4L2′B3 
                 475 
                 A2L4C4L2′B1′ 
               
               
                 178 
                 A1L5C4L2′B1 
                 476 
                 A2L4C4L2′B2 
               
               
                 179 
                 A1L5C4L2′B1′ 
                 477 
                 A2L4C4L2′B3 
               
               
                 180 
                 A1L5C4L2′B2 
                 478 
                 A2L5C4L2′B1 
               
               
                 181 
                 A1L5C4L2′B3 
                 479 
                 A2L5C4L2′B1′ 
               
               
                 182 
                 A1′L4C4L2′B1 
                 480 
                 A2L5C4L2′B2 
               
               
                 183 
                 A1′L4C4L2′B1′ 
                 481 
                 A2L5C4L2′B3 
               
               
                 184 
                 A1′L4C4L2′B2 
                 482 
                 A1′L4C4L2′B4 
               
               
                 185 
                 A1′L4C4L2′B3 
                 483 
                 A1′L5C4L2′B4 
               
               
                 186 
                 A2L4C4L2′B4 
                 484 
                 AFL5C1′L2B1 
               
               
                 187 
                 A2L5C4L2′B4 
                 485 
                 AFL5C1′L2B1′ 
               
               
                 188 
                 A1L4C4L2′B4 
                 486 
                 A1′L5C1′L2B2 
               
               
                 189 
                 A1L5C4L2′B4 
                 487 
                 AFL5C1′L2B3 
               
               
                 190 
                 A1L4C1L2B1 
                 488 
                 A1′L5C2L2B1 
               
               
                 191 
                 A1L4C1L2B1′ 
                 489 
                 A1′L5C2L2B1′ 
               
               
                 192 
                 A1L4C1L2B2 
                 490 
                 A1′L5C2L2B2 
               
               
                 193 
                 A1L4C1L2B3 
                 491 
                 A1′L5C2L2B3 
               
               
                 194 
                 A1L4C1′L2B1 
                 492 
                 A2L4C1L2B1 
               
               
                 195 
                 A1L4C1′L2B1′ 
                 493 
                 A2L4C1L2B1′ 
               
               
                 196 
                 A1L4C1I2B2 
                 494 
                 A2L4C1L2B2 
               
               
                 197 
                 A1L4C1I2B3 
                 495 
                 A2L4C1L2B3 
               
               
                 198 
                 A1L4C2L2B1 
                 496 
                 A2L4C1′L2B1 
               
               
                 199 
                 A1L4C2L2B1′ 
                 497 
                 A2L4C1′L2B1′ 
               
               
                 200 
                 A1L4C2L2B2 
                 498 
                 A2L4C1′L2B2 
               
               
                 201 
                 A1L4C2L2B3 
                 499 
                 A2L4C1′L2B3 
               
               
                 202 
                 A1L5C1L2B1 
                 500 
                 A2L4C2L2B1 
               
               
                 203 
                 A1L5C1L2B1′ 
                 501 
                 A2L4C2L2B1′ 
               
               
                 204 
                 A1L5C1L2B2 
                 502 
                 A2L4C2L2B2 
               
               
                 205 
                 A1L5C1L2B3 
                 503 
                 A2L4C2L2B3 
               
               
                 206 
                 A1L5C1′L2B1 
                 504 
                 A2L5C1L2B1 
               
               
                 207 
                 A1L5C1′L2B1′ 
                 505 
                 A2L5C1L2B1′ 
               
               
                 208 
                 A1L5C1′L2B2 
                 506 
                 A2L5C1L2B2 
               
               
                 209 
                 A1L5C1′L2B3 
                 507 
                 A2L5C1L2B3 
               
               
                 210 
                 A1L5C2L2B1 
                 508 
                 A2L5C1′L2B1 
               
               
                 211 
                 A1L5C2L2B1′ 
                 509 
                 A2L5C1′L2B1′ 
               
               
                 212 
                 A1L5C2L2B2 
                 510 
                 A2L5C1′L2B2 
               
               
                 213 
                 A1L5C2L2B3 
                 511 
                 A2L5C1′L2B3 
               
               
                 214 
                 A1′L4C1L2B1 
                 512 
                 A2L5C2L2B1 
               
               
                 215 
                 A1′L4C1L2B1′ 
                 513 
                 A2L5C2L2B1′ 
               
               
                 216 
                 A1′L4C1L2B2 
                 514 
                 A2L5C2L2B2 
               
               
                 217 
                 A1′L4C1L2B3 
                 515 
                 A2L5C2L2B3 
               
               
                 218 
                 A1′L4C1′L2B1 
                 516 
                 A1L4C1L2B4 
               
               
                 219 
                 A1′L4C1′L2B1′ 
                 517 
                 A1L4C1I2B4 
               
               
                 220 
                 A1′L4C1′L2B2 
                 518 
                 A1L4C2L2B4 
               
               
                 221 
                 A1′L4C1′L2B3 
                 519 
                 A1L5C1L2B4 
               
               
                 222 
                 A1′L4C2L2B1 
                 520 
                 A1L5C1′L2B4 
               
               
                 223 
                 A1′L4C2L2B1′ 
                 521 
                 A1L5C2L2B4 
               
               
                 224 
                 A1′L4C2L2B2 
                 522 
                 A1′L4C1L2B4 
               
               
                 225 
                 A1′L4C2L2B3 
                 523 
                 A1′L4C1′L2B4 
               
               
                 226 
                 A1′L5C1L2B1 
                 524 
                 A1′L4C2L2B4 
               
               
                 227 
                 A1′L5C1L2B1′ 
                 525 
                 A1′L5C1L2B4 
               
               
                 228 
                 A1′L5C1L2B2 
                 526 
                 A1′L5C1′L2B4 
               
               
                 229 
                 A1′L5C1L2B3 
                 527 
                 A1′L5C2L2B4 
               
               
                 230 
                 A2L4C1L2B4 
                 528 
                 A1′L5C1′L2′B1 
               
               
                 231 
                 A2L4C1′L2B4 
                 529 
                 A1′L5C1′L2′B1′ 
               
               
                 232 
                 A2L4C2L2B4 
                 530 
                 A1′L5C1′L2′B2 
               
               
                 233 
                 A2L5C1L2B4 
                 531 
                 A1′L5C1′L2′B3 
               
               
                 234 
                 A2L5C1′L2B4 
                 532 
                 A1′L5C2L2′B1 
               
               
                 235 
                 A2L5C2L2B4 
                 533 
                 A1′L5C2L2′B1′ 
               
               
                 236 
                 A1L4C1L2′B1 
                 534 
                 A1′L5C2L2′B2 
               
               
                 237 
                 A1L4C1L2′B1′ 
                 535 
                 A1′L5C2L2′B3 
               
               
                 238 
                 A1L4C1L2′B2 
                 536 
                 A2L4C1L2′B1 
               
               
                 239 
                 A1L4C1L2′B3 
                 537 
                 A2L4C1L2′B1′ 
               
               
                 240 
                 A1L4C1′L2′B1 
                 538 
                 A2L4C1L2′B2 
               
               
                 241 
                 A1L4C1′L2′B1′ 
                 539 
                 A2L4C1L2′B3 
               
               
                 242 
                 A1L4C1′L2′B2 
                 540 
                 A2L4C1′L2′B1 
               
               
                 243 
                 A1L4C1′L2′B3 
                 541 
                 A2L4C1′L2′B1′ 
               
               
                 244 
                 A1L4C2L2′B1 
                 542 
                 A2L4C1′L2′B2 
               
               
                 245 
                 A1L4C2L2′B1′ 
                 543 
                 A2L4C1′L2′B3 
               
               
                 246 
                 A1L4C2L2′B2 
                 544 
                 A2L4C2L2′B1 
               
               
                 247 
                 A1L4C2L2′B3 
                 545 
                 A2L4C2L2′B1′ 
               
               
                 248 
                 A1L5C1L2′B1 
                 546 
                 A2L4C2L2′B2 
               
               
                 249 
                 A1L5C1L2′B1′ 
                 547 
                 A2L4C2L2′B3 
               
               
                 250 
                 A1L5C1L2′B2 
                 548 
                 A2L5C1L2′B1 
               
               
                 251 
                 A1L5C1L2′B3 
                 549 
                 A2L5C1L2′B1′ 
               
               
                 252 
                 A1L5C1′L2′B1 
                 550 
                 A2L5C1L2′B2 
               
               
                 253 
                 A1L5C1′L2′B1′ 
                 551 
                 A2L5C1L2′B3 
               
               
                 254 
                 A1L5C1′L2′B2 
                 552 
                 A2L5C1′L2′B1 
               
               
                 255 
                 A1L5C1′L2′B3 
                 553 
                 A2L5C1′L2′B1′ 
               
               
                 256 
                 A1L5C2L2′B1 
                 554 
                 A2L5C1′L2′B2 
               
               
                 257 
                 A1L5C2L2′B1′ 
                 555 
                 A2L5C1′L2′B3 
               
               
                 258 
                 A1L5C2L2′B2 
                 556 
                 A2L5C2L2′B1 
               
               
                 259 
                 A1L5C2L2′B3 
                 557 
                 A2L5C2L2′B1′ 
               
               
                 260 
                 A1′L4C1L2′B1 
                 558 
                 A2L5C2L2′B2 
               
               
                 261 
                 A1′L4C1L2′B1′ 
                 559 
                 A2L5C2L2′B3 
               
               
                 262 
                 A1′L4C1L2′B2 
                 560 
                 A1L4C1L2′B4 
               
               
                 263 
                 A1′L4C1L2′B3 
                 561 
                 A1L4C1′L2′B4 
               
               
                 264 
                 A1′L4C1′L2′B1 
                 562 
                 A1L4C2L2′B4 
               
               
                 265 
                 A1′L4C1′L2′B1′ 
                 563 
                 A1L5C1L2′B4 
               
               
                 266 
                 A1′L4C1′L2′B2 
                 564 
                 A1L5C1′L2′B4 
               
               
                 267 
                 A1′L4C1′L2′B3 
                 565 
                 A1L5C2L2′B4 
               
               
                 268 
                 A1′L4C2L2′B1 
                 566 
                 A1′L4C1L2′B4 
               
               
                 269 
                 A1′L4C2L2′B1′ 
                 567 
                 A1′L4C1′L2′B4 
               
               
                 270 
                 A1′L4C2L2′B2 
                 568 
                 A1′L4C2L2′B4 
               
               
                 271 
                 A1′L4C2L2′B3 
                 569 
                 A1′L5C1L2′B4 
               
               
                 272 
                 A1′L5C1L2′B1 
                 570 
                 A1′L5C1′L2′B4 
               
               
                 273 
                 A1L5C1L2′B1′ 
                 571 
                 A1′L5C2L2′B4 
               
               
                 274 
                 A1′L5C1L2′B2 
                 572 
                 A2L4C4L1B4 
               
               
                 275 
                 A1′L5C1L2′B3 
                 573 
                 A2L4C4L1′B4 
               
               
                 276 
                 A2L4C1L2′B4 
                 574 
                 A2L5C4L1B4 
               
               
                 277 
                 A2L4C1′L2′B4 
                 575 
                 A2L5C4L1′B4 
               
               
                 278 
                 A2L4C2L2′B4 
                 576 
                 A1′L5C4L1B1 
               
               
                 279 
                 A2L5C1L2′B4 
                 577 
                 A1′L5C4L1B1′ 
               
               
                 280 
                 A2L5C1′L2′B4 
                 578 
                 A1′L5C4L1B2 
               
               
                 281 
                 A2L5C2L2′B4 
                 579 
                 A1′L5C4L1B3 
               
               
                 282 
                 A2L4C4L1B1 
                 580 
                 A1′L5C4L1′B1 
               
               
                 283 
                 A2L4C4L1B1′ 
                 581 
                 A1′L5C4L1′B1′ 
               
               
                 284 
                 A2L4C4L1B2 
                 582 
                 A1′L5C4L1′B2 
               
               
                 285 
                 A2L4C4L1B3 
                 583 
                 A1′L5C4L1′B3 
               
               
                 286 
                 A2L4C4L1′B1 
                 584 
                 A1′L5C4L1B4 
               
               
                 287 
                 A2L4C4L1′B1′ 
                 585 
                 A1′L5C4L1′B4 
               
               
                 288 
                 A2L4C4L1′B2 
                 586 
                 A1L5C4L1B1 
               
               
                 289 
                 A2L4C4L1′B3 
                 587 
                 A1L5C4L1B1′ 
               
               
                 290 
                 A2L5C4L1B1 
                 588 
                 A1L5C4L1B2 
               
               
                 291 
                 A2L5C4L1B1′ 
                 589 
                 A1L5C4L1B3 
               
               
                 292 
                 A2L5C4L1B2 
                 590 
                 A1L5C4L1′B1 
               
               
                 293 
                 A2L5C4L1B3 
                 591 
                 A1L5C4L1′B1′ 
               
               
                 294 
                 A2L5C4L1′B1 
                 592 
                 A1L5C4L1′B2 
               
               
                 295 
                 A2L5C4L1′B1′ 
                 593 
                 A1L5C4L1′B3 
               
               
                 296 
                 A2L5C4L1′B2 
                 594 
                 A1L5C4L1B4 
               
               
                 297 
                 A2L5C4L1′B3 
                 595 
                 A1L5C4L1′B4 
               
               
                 298 
                 A1′L4C4L1B3 
                 596 
                 A1L4C4L1B3 
               
               
                 299 
                 A1′L4C4L1′B3 
                 597 
                 A1L4C4L1′B3 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 2 
               
               
                   
               
               
                 Formulas of Additional Active Compounds 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 598 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 599 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 600 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 601 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 602 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 603 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 604 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 605 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 606 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 607 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 608 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 609 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 610 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 611 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 612 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 613 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 614 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 615 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 616 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 617 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 618 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 619 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 620 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 621 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 622 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 623 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 624 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 625 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 626 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 627 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 628 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 629 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 630 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 631 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 632 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 633 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 634 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 635 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 636 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 637 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 638 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 639 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 640 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 641 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 642 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 643 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 644 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 645 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 646 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 647 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 648 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 649 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 650 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 651 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 652 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 653 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Formula 654 
               
               
                   
                   
               
            
           
         
       
     
     Additionally, the disclosure includes compounds and salts of Formula I, Formula I′ and Formula I″ and pharmaceutically acceptable salts and compositions thereof, and any of their subformulae (2-654) in which at least one of the following conditions is met in the embodiments described below. 
     The R 12  and R 13  Amide Substituents 
     The invention includes a compound of Formula I, Formula I′ or Formula I″, a pharmaceutically acceptable salt or composition thereof, wherein R 12  or R 13  on the A1 or A2 group is an amide substituent, for example, R 32 . 
     One of R 12  and R 13  is selected from R 31  and the other of R 12  and R 13  is selected from R 32 . In another embodiment, each of R 12  and R 13  can be independently selected from R 32 . 
     R 31  is selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, —COOH, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, —C(O)OR 9 , 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 which R 31  other than hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, —COOH, —CONH 2  C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy, and each of which R 31  is also optionally substituted with one substituent selected from phenyl and 4- to 7-membered heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; which phenyl or 4- to 7-membered heterocycle is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, (mono- and di-C 1 -C 6 alkylamino)C 0 -C 4 alkyl, C 1 -C 6 alkylester, —C 0 -C 4 alkyl)(C 3 -C 7 cycloalkyl), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; 
     R 32  is selected from C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , each of which can be optionally substituted. 
     In certain embodiments, R 32  is selected from a moiety in  FIG.  15     
     Non-Limiting R 12 /R 13  Embodiments 
     In one embodiment, R 12  is R 32 . 
     In one embodiment, R 13  is R 32 . 
     In one embodiment, R 12  is R 32 , which is —C(O)NR 21 R 71 . 
     In one embodiment, R 12  is R 32 , which is —C(O)NR 24 R 25 . 
     In one embodiment, R 12  is R 32 , which is —C(O)NR 9 R 71 . 
     In one embodiment, R 12  is R 32 , which is —C(O)NR 21 SO 2 R 22 . 
     In one embodiment, R 12  is R 32 , which is —NR 9 C(O)OR 10 . 
     In one embodiment, R 12  is R 32 , which is —NR 9 C(O)OR 23 . 
     In one embodiment, R 12  is R 32 , which is —NR 9 C(O)R 21 . 
     In one embodiment, R 12  is R 32 , which is —NR 9 C(O)NR 9 R 10 . 
     In one embodiment, R 12  is R 32 , which is —NR 9 C(O)NR 10 R 23 . 
     In one embodiment, R 12  is R 32 , which is —NR 9 C(O)NR 24 R 25 . 
     In one embodiment, the disclosure provides compounds of Formula I, wherein; 
     one of R 12  and R 13  is H and the other of R 12  and R 13  is R 32 , where 
     R 32  is selected from C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , each of which can be optionally substituted. 
     In another embodiment, the disclosure provides compounds of Formula I and Formula I″, wherein; 
     R 1 , R 1′ , R 2 , and R 3′  are all hydrogen; 
     R 2  is fluoro and R 3  is hydrogen, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), or —O—C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl); 
     R 5  is hydrogen, halogen, or C 1 -C 2 alkyl; 
     R 11 , R 13 , R 14 , and R 15  if present, are independently selected at each occurrence from hydrogen, halogen, hydroxyl, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —C 0 -C 2 alkyl(mono- and di-C 1 -C 2 alkylamino), trifluoromethyl, and trifluoromethoxy; 
     X 12  is CR 12 ; and 
     R 12  is selected from C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , each of which can be optionally substituted. 
     In one embodiment, the disclosure provides compounds of Formula I, wherein; 
     m is 0 or 1; 
     R 2  is halogen, R 2′  is hydrogen or halogen, and R 3  is hydrogen, halogen, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), or —O—C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl); 
     R 6  is —C(O)C 1 -C 4 alkyl, —C(O)NH 2 , —C(O)CF 3 , —C(O)(C 3 -C 7 cycloalkyl), or -ethyl(cyanoimino); 
     one of R 12  and R 13  is selected from hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, trifluoromethyl, and trifluoromethoxy; the other of R 12  and R 13  is R 32 , where 
     R 32  is selected from C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , which can be optionally substituted. 
     In one embodiment, the disclosure provides compounds of Formula I, wherein; 
     one of R 2  and R 3  is hydrogen, hydroxyl, halogen, methyl, or methoxy; and the other of R 2  and R 13  is R 32 , where is selected from C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , each of which can be optionally substituted. 
     In one embodiment, R 32  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, —CONH 2 , —P(O)(OH) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —C 0 -C 2 alkyl(mono- and di-C 1 -C 4 alkylamino), C 1 -C 6 alkylester, C 1 -C 4 alkylamino, C 1 -C 4 hydroxylalkyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy. 
     Central Core Moiety 
     The central core moiety, C, in Formula I is described below. 
     C is C1, C1′, C2, C3 or C4. 
     C1, C1′, C2, C3 and C4 are described in the summary section. 
     Non-Limiting Central Core Embodiments 
     In certain embodiments, R 1  and R 1′  or R 3  and R 3′  may be 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; R 2  and R 2′  may be taken together to form a 3- to 6-membered carbocyclic spiro ring; or R 2  and R 2′  may be taken together to form a 3- to 6-membered heterocyclic spiro ring; each of which ring may be unsubstituted or substituted with 1 or more substituents independently selected from halogen (and in particular F), hydroxyl, cyano, —COOH, C 1 -C 4 alkyl (including in particular methyl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 2 -C 4 alkanoyl, hydroxyC 1 -C 4 alkyl, (mono- and di-C 1 -C 4 alkylamino)C 0 -C 4 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —O—C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy. 
     In other embodiments, R 1  and R 2  may be taken together to form a 3-membered carbocyclic ring; R 1  and R 2  may be taken together to form a 4, 5 or 6-membered carbocyclic or an aryl ring or a 4, 5 or 6 membered heterocyclic or heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, O, and S; or R 2  and R 3 , if bound to adjacent carbon atoms, may be taken together to form a 3- to 6-membered carbocyclic or aryl ring or a 3- to 6-membered heterocyclic or heteroaryl ring; 
     each of which ring may be unsubstituted or substituted with 1 or more substituents independently selected from halogen (and in particular F), hydroxyl, cyano, —COOH, C 1 -C 4 alkyl (including in particular methyl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 2 -C 4 alkanoyl, hydroxyC 1 -C 4 alkyl, (mono- and di-C 1 -C 4 alkylamino)C 0 -C 4 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —O—C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy. 
     In one embodiment, the central core moiety is proline. 
     In one embodiment, the central core moiety is 4-fluoroproline. 
     In one embodiment, R 1 , R 1′ , R 2′ , R 3  and R 3′ , if present, are all hydrogen; and R 2  is fluoro. 
     In one embodiment, R 1 , R 1′ , R 2′ , and R 3′ , if present, are all hydrogen; and R 2  is fluoro and R 3  is —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl) or —O—C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl). 
     In one embodiment, R 1  and R 2  are taken together to form a 3- to 6-membered cycloalkyl group, and R 1′ , R 2′ , R 3 , and R 3′ , where present, are all hydrogen. In one embodiment, the bicycle is fused in a cis fashion. In one embodiment, the bicyclic ring is fused in a trans fashion. 
     In one embodiment, R 1  and R 2  are taken together to form a 3- to 6-membered cycloalkyl group, and R 1′ , R 2′ , R 3 , and R 3′ , where present, are all hydrogen. [please add reference to both stereospecific embodiments] 
     In one embodiment, R 1  and R 2  are taken together to form a 3- to 6-membered cycloalkyl group that is cis with respect to the carboxyl group of L-proline as shown below: 
     
       
         
         
             
             
         
       
     
     In one embodiment, R 1  and R 2  are taken together to form a 3- to 6-membered cycloalkyl group that is trans with respect to the carboxyl group of L-proline as shown below: 
     
       
         
         
             
             
         
       
     
     In one embodiment, R 1 , R 1′ , R 3 , and R 3′ , if present, are all hydrogen, and R 2  and R 2′  are taken together to form a 5- or 6-membered heterocycloalkyl group having 1 or 2 oxygen atoms. 
     In one embodiment, R 1  is hydrogen and R 2  is fluoro. 
     In one embodiment, R 1  and R 2  are joined to form a 3 membered ring. 
     In one embodiment, R 1  and R 2  are taken together to form a 3-membered cycloalkyl group that is cis with respect to the carboxyl group of L-proline as shown below: 
     
       
         
         
             
             
         
       
     
     In one embodiment, R 1  and R 2  are taken together to form a 3-membered cycloalkyl group that is trans with respect to the carboxyl group of L-proline as shown below: 
     
       
         
         
             
             
         
       
     
     In one embodiment, R 2  and R 3  are taken together to form a 3- to 6-membered cycloalkyl group, and R 1 , R 1′ , R 2′  and R 3′ , where present, are selected from hydrogen, C 1 -C 3  alkyl or C 1 -C 3  alkoxy. 
     In one embodiment, R 2  and R 3  are taken together to form a 3- to 6-membered cycloalkyl group that is cis with respect to the carboxyl group of L-proline as shown below: 
     
       
         
         
             
             
         
       
     
     In one embodiment, R 2  and R 3  are taken together to form a 3- to 6-membered cycloalkyl group that is trans with respect to the carboxyl group of L-proline as shown below: 
     
       
         
         
             
             
         
       
     
     In one embodiment, R 2  and R 3  are taken together to form a 3-membered cycloalkyl group that is cis with respect to the carboxyl group of L-proline as shown below: 
     
       
         
         
             
             
         
       
     
     In one embodiment, R 2  and R 3  are taken together to form a 3-membered cycloalkyl group that is trans with respect to the carboxyl group of L-proline as shown below: 
     
       
         
         
             
             
         
       
     
     In one embodiment, R 1 , R 1′ , R 3 , and R 3′ , if present, are all hydrogen, and R 2  and R 2′  are taken together to form a 5- or 6-membered heterocycloalkyl group having 1 or 2 oxygen atoms. 
     In one embodiment, R 1  is hydrogen and R 2  is fluoro. 
     In one embodiment, R 1  and R 2  are joined to form a 3 membered ring. please add reference to both stereospecific embodiments] 
     The disclosure includes compounds of Formula I in which the central pyrrolidine is vinyl substituted, for example: 
     
       
         
         
             
             
         
       
     
     In one embodiment, the compound of Formula I has the structure: 
     
       
         
         
             
             
         
       
     
     In one embodiment, the central pyrrolidine is modified by addition of a second heteroatom to a pyrrolidine ring, such as N, O, S, or Si, for example: 
     
       
         
         
             
             
         
       
     
     Another modification within the scope of the disclosure is joining a substituent on the central pyrrolidine ring to R 7  or R 8  to form a 5- to 6-membered heterocyclic ring, for example: 
     
       
         
         
             
             
         
       
     
     Example compounds having the modifications disclosed above include: 
                         
Central Core L-B Substituents
 
     Illustrative central core L substituents and B substituents in Formula I are described below. 
     L is selected from L1, L1′, L2 and L2′. 
     L1 is a bond or is selected from the formulas: 
                         
where R 17  is hydrogen, C 1 -C 6 alkyl, or —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl) and R 18  and R 18′  are independently selected from hydrogen, halogen, hydroxymethyl, and methyl; and m is 0, 1, 2, or 3.
 
     L2 and L2′ are described in the summary section. 
     B is selected from B1, B1′, B2, B3 and B4 which are described in the summary section. 
     In one embodiment, -L1-B1- is 
                         
where
 
R 26  and R 27  are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, 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), C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, and C 1 -C 2 haloalkylthio.
 
Non-Limiting L-B Embodiments
 
     In one embodiment, -L1-B1- is: 
                                           
wherein
 
     R 18  and R 18′  are independently selected from hydrogen, halogen, hydroxymethyl, and methyl; and m is 0 or 1; and 
     R 26 , R 27 , and R 28  are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, 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); each of which 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, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl-, and C 1 -C 2 haloalkoxy; and 
     R 29  is hydrogen, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl or —Si(CH 3 ) 2 C(CH 3 ) 3 . 
     In one embodiment, -L-B1- moiety is selected: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In one embodiment, -L1-B1- moiety is selected: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In one embodiment, -L2-B1- moiety is selected: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In one embodiment, -L2′-B1- moiety is selected: 
     
       
         
         
             
             
         
       
     
     In one embodiment, m is 0. 
     In one embodiment, the disclosure further includes compounds and salts of Formula I in which B1 is 2-fluoro-3-chlorophenyl. In another embodiment, another carbocyclic, aryl, heterocyclic, or heteroaryl group such as 2-bromo-pyridin-6-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl, 2,2-dichlorocyclopropylmethyl, or 2-fluoro-3-trimethylsilylphenyl is used. 
     In another embodiment, B1 is phenyl, pyridyl, or indanyl each of which is unsubstituted or substituted with one or more substituents independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl (including methyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, 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, —C 0 -C 4 alkoxy(C 3 -C 7 cycloalkyl), (phenyl)C 0 -C 2 alkyl, (pyridyl)C 0 -C 2 alkyl; each of which substituents other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, —OSi(CH 3 ) 2 C(CH 3 ) 3 , —Si(CH 3 ) 2 C(CH 3 ) 3 , C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy. 
     In another embodiment, B1 is phenyl or pyridyl substituted with 1, 2, or 3 substituents selected from chloro, bromo, hydroxyl, —SCF 3 , C 1 -C 2 alkyl, C 1 -C 2 alkoxy, trifluoromethyl, phenyl and trifluoromethoxy each of which substituents other than chloro, bromo, hydroxyl, —SCF 3 , can be optionally substituted. 
     In certain embodiments, B1 is a 2-fluoro-3-chlorophenyl or a 2-fluoro-3-trifluoromethoxyphenyl group. 
     In one embodiment, B1 is pyridyl, optionally substituted with halogen, C 1 -C 2 alkoxy, and trifluoromethyl. 
     In one embodiment, B1 is phenyl, substituted with 1, 2, or 3 substituents independently selected from halogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, trifluoromethyl, and optionally substituted phenyl. 
     In one embodiment, R 23  is independently selected at each occurrence from (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (phenyl)C 0 -C 4 alkyl, (4- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl having 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 having 1, 2, or 3 heteroatoms independently selected from N, O, and S. 
     In one embodiment, L1-B3 is: 
     
       
         
         
             
             
         
       
     
     R 27′ , and R 28′  are independently selected from hydrogen, fluoro, bromo, iodo, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 2 -C 6 alkoxy, C 2 -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); each of which R 27′ , and R 28′  other than hydrogen, fluoro, bromo, iodo, hydroxyl, nitro, and cyano, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl-, and C 1 -C 2 haloalkoxy. 
     Central Core (L3)-A Substituent 
     The central core (L3)-A substituent in Formula I is described below. 
     L3 is selected from L4 and L5; 
     L4 is —C(O)—. 
     L5 is described above in the summary section. 
     A is selected from A1, A1′ and A2. 
     A1, A1′ and A2 are described above in the summary section. 
     In one embodiment, R 5  and R 6  are independently selected from —CHO, —C(O)NH 2 , —C(O)NH(CH 3 ), C 2 -C 6 alkanoyl, and hydrogen. 
     In one embodiment, each R 5  and R 6  other than hydrogen, hydroxyl, cyano, and —COOH is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, imino, cyano, cyanoimino, C 1 -C 2 alkyl, C 1 -C 4 alkoxy, —C 0 -C 2 alkyl(mono- and di-C 1 -C 4 alkylamino), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy. 
     In one embodiment, R 8  and R 8′  are independently hydrogen or methyl. 
     In one embodiment, R 8  and R 8′  are hydrogen. 
     In one embodiment, R 7  is hydrogen or methyl. 
     In one embodiment, R 7  is hydrogen. 
     Embodiments of Formulas IA, IB, IC, and ID 
     To further illustrate the invention, various embodiments of Formula IA, IB, IC and ID are provided. These are presented by way of example to show some of the variations among presented compounds within the invention, can be applied to any of the Formulas herein, and are not intended to limit the invention. 
     In one aspect, this disclosure includes compounds and salts of Formula IA: 
                         
where
 
R 6 , R 13 , and B3 may carry any of the definitions set forth herein for this variable.
 
     In another aspect, this disclosure includes compounds and salts of Formula IB, IC, and ID. 
     
       
         
         
             
             
         
       
     
     In Formulas IA, IB, IC, and ID, the variables may include any of the definitions set forth herein that results in a stable compound. In certain embodiments, the following conditions apply for Formula IB and IC. 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=0, R 1  is H, R 2  is F, R 6  is alkanoyl, R 12  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , R 13  is H, and B3 is dihydroindole. 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=0, R 1  and R 2  are joined to form a 3 membered ring, R 6  is alkanoyl, R 12  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , R 13  is H, and B3 is dihydroindole. 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=0, R 1  is H, R 2  is F, R 6  is amide, R 12  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , R 13  is H, and B3 is dihydroindole. 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=0, R 1  and R 2  are joined to form a 3 membered ring, R 6  is amide, R 12  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , R 13  is H, and B3 is dihydroindole. 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=0, R 1  is H, R 2  is F, R 6  is alkanoyl, R 12  is H, R 13  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 113 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , and B3 is dihydroindole. 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=0, R 1  and R 2  are joined to form a 3 membered ring, R 6  is alkanoyl, R 12  is H, R 13  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , — NR 9 C(O)NR 24 R 25 , and B3 is dihydroindole. 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=0, R 1  is H, R 2  is F, R 6  is amide, R 12  is H, R 13  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , and B3 is dihydroindole. 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=0, R 1  and R 2  are joined to form a 3 membered ring, R 6  is amide, R 12  is H, R 13  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , and B3 is dihydroindole 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=0, R 1  is H, R 2  is F, R 6  is alkanoyl, R 12  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , R 13  is H, and B3 is phenyl substituted with SF 5 . 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=0, R 1  and R 2  are joined to form a 3 membered ring, R 6  is alkanoyl, R 12  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , R 13  is H, and B3 is phenyl substituted with SF 5 . 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=0, R 1  is H, R 2  is F, R 6  is amide, R 12  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , R 13  is H, and B3 is phenyl substituted with SF 5 . 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=0, R 1  and R 2  are joined to form a 3 membered ring, R 6  is amide, R 12  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , R 13  is H, and B3 is phenyl substituted with SF 5 . 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=0, R 1  is H, R 2  is F, R 6  is alkanoyl, R 12  is H, R 13  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O))NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , and B3 is phenyl substituted with SF 5 . 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=0, R 1  and R 2  are joined to form a 3 membered ring, R 6  is alkanoyl, R 12  is H, R 13  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , and B3 is phenyl substituted with SF 5 . 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=0, R 1  is H, R 2  is F, R 6  is amide, R 12  is H, R 13  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , and B3 is phenyl substituted with SF 5 . 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=0, R 1  and R 2  are joined to form a 3 membered ring, R 6  is amide, R 12  is H, R 13  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , and B3 is phenyl substituted with SF 5 . 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=1, R 1  is H, R 2  is F, R 6  is alkanoyl, R 12  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 23 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , R 13  is H, and B3 is dihydroindole. 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=1, R 1  and R 2  are joined to form a 3 membered ring, R 6  is alkanoyl, R 12  is R 32 , R 32  is 
     C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , R 13  is H, and B3 is dihydroindole. 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=1, R 1  is H, R 2  is F, R 6  is amide, R 12  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , R 13  is H, and B3 is dihydroindole. 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=1, R 1  and R 2  are joined to form a 3 membered ring, R 6  is amide, R 12  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , R 13  is H, and B3 is dihydroindole. 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=1, R 1  is H, R 2  is F, R 6  is alkanoyl, R 12  is H, R 13  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , and B3 is dihydroindole. 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=1, R 1  and R 2  are joined to form a 3 membered ring, R 6  is alkanoyl, R 12  is H, R 13  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , and B3 is dihydroindole. 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=1, R 1  is H, R 2  is F, R 6  is amide, R 12  is H, R 13  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , and B3 is dihydroindole. 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=1, R 1  and R 2  are joined to form a 3 membered ring, R 6  is amide, R 12  is H, R 13  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , and B3 is dihydroindole. 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=1, R 1  is H, R 2  is F, R 6  is alkanoyl, R 12  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , R 13  is H, and B3 is phenyl substituted with SF 5 . 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=1, R 1  and R 2  are joined to form a 3 membered ring, R 6  is alkanoyl, R 2  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , R 13  is H, and B3 is phenyl substituted with SF 5 . 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=1, R 1  is H, R 2  is F, R 6  is amide, R 12  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , R 13  is H, and B3 is phenyl substituted with SF 5 . 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=1, R 1  and R 2  are joined to form a 3 membered ring, R 6  is amide, R 12  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , R 13  is H, and B3 is phenyl substituted with SF 5 . 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=1, R 1  is H, R 2  is F, R 6  is alkanoyl, R 12  is H, R 3  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , and B3 is phenyl substituted with SF 5 . 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=1, R 1  and R 2  are joined to form a 3 membered ring, R 6  is alkanoyl, R 2  is H, R 3  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , and B3 is phenyl substituted with SF 5 . 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=1, R 1  is H, R 2  is F, R 6  is amide, R 12  is H, R 13  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , and B3 is phenyl substituted with SF 5 . 
     In some embodiments, structures are provided including Formulas IB and IC, wherein m=1, R 1  and R 2  are joined to form a 3 membered ring, R 6  is amide, R 12  is H, R 13  is R 32 , R 32  is C(O)NR 21 R 71 , —C(O)NR 24 R 25 , —C(O)NR 9 R 71 , —C(O)NR 21 SO 2 R 22 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , — NR 9 C(O)NR 10 R 23 , —NR 9 C(O)NR 24 R 25 , 
     and B3 is phenyl substituted with SF 5 . 
     Embodiments of Formula 606 
     To further illustrate the invention, various embodiments of Formula 606 are disclosed. In one aspect, the disclosure includes compounds and salts of Formula 606: 
                         
wherein:
 
     R 1 , R 1′ , R 2 , R 2′ , R 3 , and R 3′  are independently selected from hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —C 0 -C 2 alkylNR 9 R 10 , —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —O—C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; 
     R 8  and R 8′  are independently selected from hydrogen, halogen, and methyl; 
     R 5  is hydrogen, hydroxyl, cyano, —COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkanoyl-C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —C(O)C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy); 
     R 6  is —C(O)CH 3 , —C(O)NH 2 , —C(O)CF 3 , —C(O)(cyclopropyl), or -ethyl(cyanoimino); and 
     R 11  and R 14  are independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, 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), —OC 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy. 
     Prodrugs of Formula I, Formula I′ and Formula I″ are also within the scope of the disclosure. 
     III. Pharmaceutical Preparations 
     Active compounds described herein can be administered to a host in need thereof as the neat chemical, but are more typically administered as a pharmaceutical composition that includes an effective amount for a host, typically a human, in need of such treatment of an active compound as described herein or its pharmaceutically acceptable salt. Thus, in one embodiment, the disclosure provides pharmaceutical compositions comprising an effective amount of compound or pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier for any of the uses described herein. The pharmaceutical composition may contain a compound or salt as the only active agent, or, in an alternative embodiment, the compound and at least one additional active agent. 
     An effective amount of an active compound as described herein, or the active compound described herein in combination or alternation with, or preceded by, concomitant with or followed by another active agent, can be used in an amount sufficient to (a) inhibit the progression of a disorder mediated by the complement pathway, including an inflammatory, immune, including an autoimmune, disorder or complement Factor D related disorder; (b) cause a regression of an inflammatory, immune, including an autoimmune, disorder or complement Factor D related disorder; (c) cause a cure of an inflammatory, immune, including an autoimmune, disorder or complement Factor D related disorder; or inhibit or prevent the development of an inflammatory, immune, including an autoimmune, disorder or complement Factor D related disorder. Accordingly, an effective amount of an active compound or its salt or composition described herein will provide a sufficient amount of the active agent when administered to a patient to provide a clinical benefit. 
     The exact amount of the active compound or pharmaceutical composition described herein to be delivered to the host, typically a human, in need thereof, will be determined by the health care provider to achieve the desired clinical benefit. 
     In certain embodiments the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form. Examples are dosage forms with at least about 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, or 1700 mg of active compound, or its salt. In one embodiment, the dosage form has at least about 100 mg, 200 mg, 400 mg, 500 mg, 600 mg, 1000 mg, 1200 mg, or 1600 mg of active compound, or its salt. The amount of active compound in the dosage form is calculated without reference to the salt. The dosage form can be administered, for example, once a day (q.d.), twice a day (b.i.d.), three times a day (t.i.d.), four times a day (q.i.d.), once every other day (Q2d), once every third day (Q3d), as needed, or any dosage schedule that provides treatment of a disorder described herein. 
     The pharmaceutical composition may for example include a molar ratio of the active compound and an additional active agent that achieves the desired result. For example, the pharmaceutical composition may contain a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1 or from about 1.5:1 to about 4:1 of an additional active agent in combination with the active compound (additional active agent: active compound), or its salt, described herein. In one embodiment, the additional active agent is an anti-inflammatory or immunosuppressing agent. 
     Compounds disclosed herein or used as described herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, via implant, including ocular implant, transdermally, via buccal administration, rectally, as an ophthalmic solution, injection, including ocular injection, intravenous, intra-aortal, intracranial, subdermal, intraperitoneal, subcutaneous, transnasal, sublingual, intrathecal, or rectal or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers. For ocular delivery, the compound can be administered, as desired, for example, as a solution, suspension, or other formulation via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial, subchorodial, chorodial, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, circumcorneal, or tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion or via an ocular device, injection, or topically administered formulation, for example a solution or suspension provided as an eye drop. 
     The pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a gel cap, a pill, a microparticle, a nanoparticle, an injection or infusion solution, a capsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, a dry powder, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral formulation, or an ophthalmic solution or suspension. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose. 
     Pharmaceutical compositions, and methods of manufacturing such compositions, suitable for administration as contemplated herein are known in the art. Examples of known techniques include, for example, U.S. Pat. Nos. 4,983,593, 5,013,557, 5,456,923, 5,576,025, 5,723,269, 5,858,411, 6,254,889, 6,303,148, 6,395,302, 6,497,903, 7,060,296, 7,078,057, 7,404,828, 8,202,912, 8,257,741, 8,263,128, 8,337,899, 8,431,159, 9,028,870, 9,060,938, 9,211,261, 9,265,731, 9,358,478, and 9,387,252, incorporated by reference herein. 
     The pharmaceutical compositions contemplated here can optionally include a carrier. Carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, fillers, flavorants, glidents, lubricants, pH modifiers, preservatives, stabilizers, surfactants, solubilizers, tableting agents, and wetting agents. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils. Examples of other matrix materials, fillers, or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and starch. Examples of surface active agents include sodium lauryl sulfate and polysorbate 80. Examples of drug complexing agents or solubilizers include the polyethylene glycols, caffeine, xanthene, gentisic acid and cylodextrins. Examples of disintegrants include sodium starch gycolate, sodium alginate, carboxymethyl cellulose sodium, methyl cellulose, colloidal silicon dioxide, and croscarmellose sodium. Examples of binders include methyl cellulose, microcrystalline cellulose, starch, and gums such as guar gum, and tragacanth. Examples of lubricants include magnesium stearate and calcium stearate. Examples of pH modifiers include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, and the like; bases such as sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, and the like, and buffers generally comprising mixtures of acids and the salts of said acids. Optional other active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention. 
     In certain embodiments, the pharmaceutical composition for administration further includes a compound or salt of Formula I, I′, or I″ and optionally comprises one or more of a phosphoglyceride; phosphatidylcholine; dipalmitoyl phosphatidylcholine (DPPC); dioleylphosphatidyl ethanolamine (DOPE); dioleyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine; cholesterol; cholesterol ester; diacylglycerol; diacylglycerolsuccinate; diphosphatidyl glycerol (DPPG); hexanedecanol; fatty alcohol such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; a surface active fatty acid, such as palmitic acid or oleic acid; fatty acid; fatty acid monoglyceride; fatty acid diglyceride; fatty acid amide; sorbitan trioleate (Span®85) glycocholate; sorbitan monolaurate (Span®20); polysorbate 20 (Tween®20); polysorbate 60 (Tween®60); polysorbate 65 (Tween®65); polysorbate 80 (Tween®80); polysorbate 85 (Tween®85); polyoxyethylene monostearate; surfactin; a poloxomer; a sorbitan fatty acid ester such as sorbitan trioleate; lecithin; lysolecithin; phosphatidylserine; phosphatidylinositol; sphingomyelin; phosphatidylethanolamine (cephalin); cardiolipin; phosphatidic acid; cerebroside; dicetylphosphate; dipalmitoylphosphatidylglycerol; stearylamine; dodecylamine; hexadecyl-amine; acetyl palmitate; glycerol ricinoleate; hexadecyl sterate; isopropyl myristate; tyloxapol; poly(ethylene glycol)5000-phosphatidylethanolamine; poly(ethylene glycol)400-monostearate; phospholipid; synthetic and/or natural detergent having high surfactant properties; deoxycholate; cyclodextrin; chaotropic salt; ion pairing agent; glucose, fructose, galactose, ribose, lactose, sucrose, maltose, trehalose, cellbiose, mannose, xylose, arabinose, glucoronic acid, galactoronic acid, mannuronic acid, glucosamine, galatosamine, and neuramic acid; pullulan, cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), hydroxycellulose (HC), methylcellulose (MC), dextran, cyclodextran, glycogen, hydroxyethylstarch, carageenan, glycon, amylose, chitosan, N,O-carboxylmethylchitosan, algin and alginic acid, starch, chitin, inulin, konjac, glucommannan, pustulan, heparin, hyaluronic acid, curdlan, and xanthan, mannitol, sorbitol, xylitol, erythritol, maltitol, and lactitol, a pluronic polymer, polyethylene, polycarbonate (e.g. poly(1,3-dioxan-2one)), polyanhydride (e.g. poly(sebacic anhydride)), polypropylfumerate, polyamide (e.g. polycaprolactam), polyacetal, polyether, polyester (e.g., polylactide, polyglycolide, polylactide-co-glycolide, polycaprolactone, polyhydroxyacid (e.g. poly((β-hydroxyalkanoate))), poly(orthoester), polycyanoacrylate, polyvinyl alcohol, polyurethane, polyphosphazene, polyacrylate, polymethacrylate, polyurea, polystyrene, and polyamine, polylysine, polylysine-PEG copolymer, and poly(ethyleneimine), poly(ethylene imine)-PEG copolymer, glycerol monocaprylocaprate, propylene glycol, Vitamin E TPGS (also known as d-α-Tocopheryl polyethylene glycol 1000 succinate), gelatin, titanium dioxide, polyvinylpyrrolidone (PVP), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO/PPO), polyethyleneglycol (PEG), sodium carboxymethylcellulose (NaCMC), hydroxypropylmethyl cellulose acetate succinate (HPMCAS). 
     In some embodiments, the pharmaceutical preparation may include polymers for controlled delivery of the described compounds, including, but not limited to pluronic polymers, polyesters (e.g., polylactic acid, poly(lactic-co-glycolic acid), polycaprolactone, polyvalerolactone, poly(1,3-dioxan-2one)); polyanhydrides (e.g., poly(sebacic anhydride)); polyethers (e.g., polyethylene glycol); polyurethanes; polymethacrylates; polyacrylates; and polycyanoacrylates. In some embodiments, polymers may be modified with polyethylene glycol (PEG), with a carbohydrate, and/or with acyclic polyacetals derived from polysaccharides. See, e.g., Papisov, 2001, ACS Symposium Series, 786:301, incorporated by reference herein. 
     The compounds of the present invention can be formulated as particles. In one embodiment the particles are or include microparticles. In an alternative embodiment the particles are or include nanoparticles. 
     In an additional alternative embodiment, common techniques for preparing particles include, but are not limited to, solvent evaporation, solvent removal, spray drying, phase inversion, coacervation, and low temperature casting. Suitable methods of particle formulation are briefly described below. Pharmaceutically acceptable excipients, including pH modifying agents, disintegrants, preservatives, and antioxidants, can optionally be incorporated into the particles during particle formation. 
     In one embodiment, the particles are derived through a solvent evaporation method. In this method, a compound described herein (or polymer matrix and one or more compounds described herein) is dissolved in a volatile organic solvent, such as methylene chloride. The organic solution containing a compound described herein is then suspended in an aqueous solution that contains a surface active agent such as poly(vinyl alcohol). The resulting emulsion is stirred until most of the organic solvent evaporated, leaving solid nanoparticles or microparticles. The resulting nanoparticles or microparticles are washed with water and dried overnight in a lyophilizer. Nanoparticles with different sizes and morphologies can be obtained by this method. 
     Pharmaceutical compositions which contain labile polymers, such as certain polyanhydrides, may degrade during the fabrication process due to the presence of water. For these polymers, methods which are performed in completely or substantially anhydrous organic solvents can be used to make the particles. 
     Solvent removal can also be used to prepare particles from a compound that is hydrolytically unstable. In this method, the compound (or polymer matrix and one or more compounds) is dispersed or dissolved in a volatile organic solvent such as methylene chloride. This mixture is then suspended by stirring in an organic oil (such as silicon oil) to form an emulsion. Solid particles form from the emulsion, which can subsequently be isolated from the supernatant. The external morphology of spheres produced with this technique is highly dependent on the identity of the drug. 
     In one embodiment an active compound as described herein is administered to a patient in need thereof as particles formed by solvent removal. In another embodiment the present invention provides particles formed by solvent removal comprising a compound of the present invention and one or more pharmaceutically acceptable excipients as defined herein. In another embodiment the particles formed by solvent removal comprise a compound of the present invention and an additional therapeutic agent. In a further embodiment the particles formed by solvent removal comprise a compound of the present invention, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients. In another embodiment any of the described particles formed by solvent removal can be formulated into a tablet and then coated to form a coated tablet. In an alternative embodiment the particles formed by solvent removal are formulated into a tablet but the tablet is uncoated. 
     In one embodiment, the particles are derived by spray drying. In this method, a compound (or polymer matrix and one or more compounds) is dissolved in an organic solvent such as methylene chloride. The solution is pumped through a micronizing nozzle driven by a flow of compressed gas, and the resulting aerosol is suspended in a heated cyclone of air, allowing the solvent to evaporate from the micro droplets, forming particles. Microparticles and nanoparticles can be obtained using this method. 
     In one embodiment an active compound as described herein is administered to a patient in need thereof as a spray dried dispersion (SDD). In another embodiment the present invention provides a spray dried dispersion (SDD) comprising a compound of the present invention and one or more pharmaceutically acceptable excipients as defined herein. In another embodiment the SDD comprises a compound of the present invention and an additional therapeutic agent. In a further embodiment the SDD comprises a compound of the present invention, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients. In another embodiment any of the described spray dried dispersions can be coated to form a coated tablet. In an alternative embodiment the spray dried dispersion is formulated into a tablet but is uncoated. 
     Particles can be formed from the active compound as described herein using a phase inversion method. In this method, the compound (or polymer matrix and one or more active compounds) is dissolved in a suitable solvent, and the solution is poured into a strong non-solvent for the compound to spontaneously produce, under favorable conditions, microparticles or nanoparticles. The method can be used to produce nanoparticles in a wide range of sizes, including, for example, from nanoparticles to microparticles, typically possessing a narrow particle size distribution. 
     In one embodiment, an active compound as described herein is administered to a patient in need thereof as particles formed by phase inversion. In another embodiment the present invention provides particles formed by phase inversion comprising a compound of the present invention and one or more pharmaceutically acceptable excipients as defined herein. In another embodiment the particles formed by phase inversion comprise a compound of the present invention and an additional therapeutic agent. In a further embodiment the particles formed by phase inversion comprise a compound of the present invention, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients. In another embodiment any of the described particles formed by phase inversion can be formulated into a tablet and then coated to form a coated tablet. In an alternative embodiment the particles formed by phase inversion are formulated into a tablet but the tablet is uncoated. 
     Techniques for particle formation using coacervation are known in the art, for example, as described in GB-B-929 406; GB-B-929 40 1; and U.S. Pat. Nos. 3,266,987, 4,794,000, and 4,460,563. Coacervation involves the separation of a compound (or polymer matrix and one or more compounds) solution into two immiscible liquid phases. One phase is a dense coacervate phase, which contains a high concentration of the compound, while the second phase contains a low concentration of the compound. Within the dense coacervate phase, the compound forms nanoscale or microscale droplets, which harden into particles. Coacervation may be induced by a temperature change, addition of a non-solvent or addition of a micro-salt (simple coacervation), or by the addition of another polymer thereby forming an interpolymer complex (complex coacervation). 
     In one embodiment an active compound as described herein is administered to a patient in need thereof as particles formed by coacervation. In another embodiment the present invention provides particles formed by coacervation comprising a compound of the present invention and one or more pharmaceutically acceptable excipients as defined herein. In another embodiment the particles formed by coacervation comprise a compound of the present invention and an additional therapeutic agent. In a further embodiment the particles formed by coacervation comprise a compound of the present invention, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients. In another embodiment any of the described particles formed by coacervation can be formulated into a tablet and then coated to form a coated tablet. In an alternative embodiment the particles formed by coacervation are formulated into a tablet but the tablet is uncoated. 
     Methods for very low temperature casting of controlled release microspheres are described in U.S. Pat. No. 5,019,400 to Gombotz et al. In this method, the compound is dissolved in a solvent. The mixture is then atomized into a vessel containing a liquid non-solvent at a temperature below the freezing point of the drug solution which freezes the compound droplets. As the droplets and non-solvent for the compound are warmed, the solvent in the droplets thaws and is extracted into the non-solvent, hardening the microspheres. 
     In one embodiment, a compound of the present invention is administered to a patient in need thereof as particles formed by low temperature casting. In another embodiment the present invention provides particles formed by low temperature casting comprising a compound of the present invention and one or more pharmaceutically acceptable excipients as defined herein. In another embodiment the particles formed by low temperature casting comprise a compound of the present invention and an additional therapeutic agent. In a further embodiment the particles formed by low temperature casting comprise a compound of the present invention, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients. In another embodiment any of the described particles formed by low temperature casting can be formulated into a tablet and then coated to form a coated tablet. In an alternative embodiment the particles formed by low temperature casting are formulated into a tablet but the tablet is uncoated. 
     In one aspect of the present invention, an effective amount of an active compound as described herein is incorporated into a nanoparticle, e.g. for convenience of delivery and/or extended release delivery. The use of materials in nanoscale provides one the ability to modify fundamental physical properties such as solubility, diffusivity, blood circulation half-life, drug release characteristics, and/or immunogenicity. A number of nanoparticle-based therapeutic and diagnostic agents have been developed for the treatment of cancer, diabetes, pain, asthma, allergy, and infections. These nanoscale agents may provide more effective and/or more convenient routes of administration, lower therapeutic toxicity, extend the product life cycle, and ultimately reduce health-care costs. As therapeutic delivery systems, nanoparticles can allow targeted delivery and controlled release. 
     In addition, nanoparticle-based compound delivery can be used to release compounds at a sustained rate and thus lower the frequency of administration, deliver drugs in a targeted manner to minimize systemic side effects, or deliver two or more drugs simultaneously for combination therapy to generate a synergistic effect and suppress drug resistance. A number of nanotechnology-based therapeutic products have been approved for clinical use. Among these products, liposomal drugs and polymer-based conjugates account for a large proportion of the products. See, Zhang, L., et al., Nanoparticles in Medicine: Therapeutic Applications and Developments, Clin. Pharm. and Ther., 83(5):761-769, 2008. 
     Methods for producing nanoparticles are known in the art. For example, see Muller, R. H., et al., Solid lipid nanoparticles (SLN) for controlled drug delivery—a review of the state of the art,  Eur. H. Pharm. Biopharm.,  50:161-177, 2000; U.S. Pat. No. 8,691,750 to Consien et al.; WO 2012/145801 to Kanwar. U.S. Pat. No. 8,580,311 to Armes, S. et al.; Petros, R. A. and DeSimone, J. M., Strategies in the design of nanoparticles for therapeutic applications, Nature Reviews/Drug Discovery, vol. 9:615-627, 2010; U.S. Pat. Nos. 8,465,775; 8,444,899; 8,420,124; 8,263,129; 8,158,728; 8,268,446; Pellegrino et al., 2005, Small, 1:48; Murray et al., 2000, Ann. Rev. Mat. Sci., 30:545; and Trindade et al., 2001, Chem. Mat., 13:3843; all incorporated herein by reference. Additional methods have been described in the literature (see, e.g., Doubrow, Ed., “Microcapsules and Nanoparticles in Medicine and Pharmacy,” CRC Press, Boca Raton, 1992; Mathiowitz et al., 1987, J. Control. Release, 5:13; Mathiowitz et al., 1987, Reactive Polymers, 6:275; and Mathiowitz et al., 1988, J. Appl. Polymer Sci., 35:755; U.S. Pat. Nos. 5,578,325 and 6,007,845; P. Paolicelli et al., “Surface-modified PLGA-based Nanoparticles that can Efficiently Associate and Deliver Virus-like Particles” Nanomedicine. 5(6):843-853 (2010)), U.S. Pat. No. 5,543,158 to Gref et al., or WO publication WO2009/051837 by Von Andrian et al. Zauner et al., 1998, Adv. Drug Del. Rev., 30:97; and Kabanov et al., 1995, Bioconjugate Chem., 6:7; (PEI; Boussif et al., 1995, Proc. Natl. Acad. Sci., USA, 1995, 92:7297), and poly(amidoamine) dendrimers (Kukowska-Latallo et al., 1996, Proc. Natl. Acad. Sci., USA, 93:4897; Tang et al., 1996, Bioconjugate Chem., 7:703; and Haensler et al., 1993, Bioconjugate Chem., 4:372; Putnam et al., 1999, Macromolecules, 32:3658; Barrera et al., 1993, J. Am. Chem. Soc., 115:11010; Kwon et al., 1989, Macromolecules, 22:3250; Lim et al., 1999, J. Am. Chem. Soc., 121:5633; and Zhou et al., 1990, Macromolecules, 23:3399). Examples of these polyesters include poly(L-lactide-co-L-lysine) (Barrera et al., 1993, J. Am. Chem. Soc., 115:11010), poly(serine ester) (Zhou et al., 1990, Macromolecules, 23:3399), poly(4-hydroxy-L-proline ester) (Putnam et al., 1999, Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem. Soc., 121:5633), and poly(4-hydroxy-L-proline ester) (Putnam et al., 1999, Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem. Soc., 121:5633; U.S. Pat. Nos. 6,123,727; 5,804,178; 5,770,417; 5,736,372; 5,716,404; 6,095,148; 5,837,752; 5,902,599; 5,696,175; 5,514,378; 5,512,600; 5,399,665; 5,019,379; 5,010,167; 4,806,621; 4,638,045; and 4,946,929; Wang et al., 2001, J. Am. Chem. Soc., 123:9480; Lim et al., 2001, J. Am. Chem. Soc., 123:2460; Langer, 2000, Acc. Chem. Res., 33:94; Langer, 1999, J. Control. Release, 62:7; and Uhrich et al., 1999, Chem. Rev., 99:3181; Concise Encyclopedia of Polymer Science and Polymeric Amines and Ammonium Salts, Ed. by Goethals, Pergamon Press, 1980; Principles of Polymerization by Odian, John Wiley &amp; Sons, Fourth Edition, 2004; Contemporary Polymer Chemistry by Allcock et al., Prentice-Hall, 1981; Deming et al., 1997, Nature, 390:386; and in U.S. Pat. Nos. 6,506,577, 6,632,922, 6,686,446, and 6,818,732; C. Astete et al., “Synthesis and characterization of PLGA nanoparticles” J. Biomater. Sci. Polymer Edn, Vol. 17, No. 3, pp. 247-289 (2006); K. Avgoustakis “Pegylated Poly(Lactide) and Poly(Lactide-Co-Glycolide) Nanoparticles: Preparation, Properties and Possible Applications in Drug Delivery” Current Drug Delivery 1:321-333 (2004); C. Reis et al., “Nanoencapsulation I. Methods for preparation of drug-loaded polymeric nanoparticles” Nanomedicine 2:8-21 (2006); P. Paolicelli et al., “Surface-modified PLGA-based Nanoparticles that can Efficiently Associate and Deliver Virus-like Particles” Nanomedicine. 5(6):843-853 (2010); U.S. Pat. No. 6,632,671 to Unger Oct. 14, 2003, all incorporated herein by reference. 
     In one embodiment, the polymeric particle is between about 0.1 nm to about 10000 nm, between about 1 nm to about 1000 nm, between about 10 nm and 1000 nm, between about 1 and 100 nm, between about 1 and 10 nm, between about 1 and 50 nm, between about 100 nm and 800 nm, between about 400 nm and 600 nm, or about 500 nm. In one embodiment, the microparticles are no more than about 0.1 nm, 0.5 nm, 1.0 nm, 5.0 nm, 10 nm, 25 nm, 50 nm, 75 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, 1000 nm, 1250 nm, 1500 nm, 1750 nm, or 2000 nm. In some embodiments, a compound described herein may be covalently coupled to a polymer used in the nanoparticle, for example a polystyrene particle, PLGA particle, PLA particle, or other nanoparticle. 
     The pharmaceutical compositions can be formulated for oral administration. These compositions can contain any amount of active compound that achieves the desired result, for example between 0.1 and 99 weight % (wt. %) of the compound and usually at least about 5 wt. % of the compound. Some embodiments contain at least about 10%, 15%, 20%, 25 wt. % to about 50 wt. % or from about 5 wt. % to about 75 wt. % of the compound. 
     Pharmaceutical compositions suitable for rectal administration are typically presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture. 
     Pharmaceutical compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof. 
     Pharmaceutical compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Pharmaceutical compositions suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. In one embodiment, microneedle patches or devices are provided for delivery of drugs across or into biological tissue, particularly the skin. The microneedle patches or devices permit drug delivery at clinically relevant rates across or into skin or other tissue barriers, with minimal or no damage, pain, or irritation to the tissue. 
     Pharmaceutical compositions suitable for administration to the lungs can be delivered by a wide range of passive breath driven and active power driven single/-multiple dose dry powder inhalers (DPI). The devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Selection of a suitable lung delivery device depends on parameters, such as nature of the drug and its formulation, the site of action, and pathophysiology of the lung. 
     Additional non-limiting examples of inhalation drug delivery devices and methods include, for example, U.S. Pat. No. 7,383,837 titled “Inhalation device” (SmithKline Beecham Corporation); WO/2006/033584 titled “Powder inhaler” (Glaxo SmithKline Pharmaceuticals SA); WO/2005/044186 titled “Inhalable pharmaceutical formulations employing desiccating agents and methods of administering the same” (Glaxo Group Ltd and SmithKline Beecham Corporation); U.S. Pat. No. 9,095,670 titled “Inhalation device and method of dispensing medicament”, U.S. Pat. No. 8,205,611 titled “Dry powder inhaler” (Astrazeneca AB); WO/2013/038170 titled “Inhaler” (Astrazeneca AB and Astrazeneca UK Ltd.); US/2014/0352690 titled “Inhalation Device with Feedback System”, U.S. Pat. No. 8,910,625 and US/2015/0165137 titled “Inhalation Device for Use in Aerosol Therapy” (Vectura GmbH); U.S. Pat. No. 6,948,496 titled “Inhalers”, US/2005/0152849 titled “Powders comprising anti-adherent materials for use in dry powder inhalers”, U.S. Pat. Nos. 6,582,678, 8,137,657, US/2003/0202944, and US/2010/0330188 titled “Carrier particles for use in dry powder inhalers”, U.S. Pat. No. 6,221,338 titled “Method of producing particles for use in dry powder inhalers”, U.S. Pat. No. 6,989,155 titled “Powders”, US/2007/0043030 titled “Pharmaceutical compositions for treating premature ejaculation by pulmonary inhalation”, U.S. Pat. No. 7,845,349 titled “Inhaler”, US/2012/0114709 and U.S. Pat. No. 8,101,160 titled “Formulations for Use in Inhaler Devices”, US/2013/0287854 titled “Compositions and Uses”, US/2014/0037737 and U.S. Pat. No. 8,580,306 titled “Particles for Use in a Pharmaceutical Composition”, US/2015/0174343 titled “Mixing Channel for an Inhalation Device”, U.S. Pat. No. 7,744,855 and US/2010/0285142 titled “Method of making particles for use in a pharmaceutical composition”, U.S. Pat. No. 7,541,022, US/2009/0269412, and US/2015/0050350 titled “Pharmaceutical formulations for dry powder inhalers” (Vectura Limited). 
     Many methods and devices for drug delivery to the eye are known in the art. Non-limiting examples are described in the following patents and patent applications (fully incorporated herein by reference). Examples are U.S. Pat. No. 8,192,408 titled “Ocular trocar assembly” (Psivida Us, Inc.); U.S. Pat. No. 7,585,517 titled “Transcleral delivery” (Macusight, Inc.); U.S. Pat. Nos. 5,710,182 and 5,795,913 titled “Ophthalmic composition” (Santen OY); U.S. Pat. No. 8,663,639 titled “Formulations for treating ocular diseases and conditions”, U.S. Pat. No. 8,486,960 titled “Formulations and methods for vascular permeability-related diseases or conditions”, U.S. Pat. Nos. 8,367,097 and 8,927,005 titled “Liquid formulations for treatment of diseases or conditions”, U.S. Pat. No. 7,455,855 titled “Delivering substance and drug delivery system using the same” (Santen Pharmaceutical Co., Ltd.); WO/2011/050365 titled “Conformable Therapeutic Shield For Vision and Pain” and WO/2009/145842 titled “Therapeutic Device for Pain Management and Vision” (Forsight Labs, LLC); U.S. Pat. Nos. 9,066,779 and 8,623,395 titled “Implantable therapeutic device”, WO/2014/160884 titled “Ophthalmic Implant for Delivering Therapeutic Substances”, U.S. Pat. Nos. 8,399,006, 8,277,830, 8,795,712, 8,808,727, 8,298,578, and WO/2010/088548 titled “Posterior segment drug delivery”, WO/2014/152959 and US20140276482 titled “Systems for Sustained Intraocular Delivery of Low Solubility Compounds from a Port Delivery System Implant”, U.S. Pat. Nos. 8,905,963 and 9,033,911 titled “Injector apparatus and method for drug delivery”, WO/2015/057554 titled “Formulations and Methods for Increasing or Reducing Mucus”, U.S. Pat. Nos. 8,715,712 and 8,939,948 titled “Ocular insert apparatus and methods”, WO/2013/116061 titled “Insertion and Removal Methods and Apparatus for Therapeutic Devices”, WO/2014/066775 titled “Ophthalmic System for Sustained Release of Drug to the Eye”, WO/2015/085234 and WO/2012/019176 titled “Implantable Therapeutic Device”, WO/2012/065006 titled “Methods and Apparatus to determine Porous Structures for Drug Delivery”, WO/2010/141729 titled “Anterior Segment Drug Delivery”, WO/2011/050327 titled “Corneal Denervation for Treatment of Ocular Pain”, WO/2013/022801 titled “Small Molecule Delivery with Implantable Therapeutic Device”, WO/2012/019047 titled “Subconjunctival Implant for Posterior Segment Drug Delivery”, WO/2012/068549 titled “Therapeutic Agent Formulations for Implanted Devices”, WO/2012/019139 titled “Combined Delivery Methods and Apparatus”, WO/2013/040426 titled “Ocular Insert Apparatus and Methods”, WO/2012/019136 titled “Injector Apparatus and Method for Drug Delivery”, WO/2013/040247 titled “Fluid Exchange Apparatus and Methods” (ForSight Vision4, Inc.). 
     Additional non-limiting examples of how to deliver the active compounds are provided in WO/2015/085251 titled “Intracameral Implant for Treatment of an Ocular Condition” (Envisia Therapeutics, Inc.); WO/2011/008737 titled “Engineered Aerosol Particles, and Associated Methods”, WO/2013/082111 titled “Geometrically Engineered Particles and Methods for Modulating Macrophage or Immune Responses”, WO/2009/132265 titled “Degradable compounds and methods of use thereof, particularly with particle replication in non-wetting templates”, WO/2010/099321 titled “Interventional drug delivery system and associated methods”, WO/2008/100304 titled “Polymer particle composite having high fidelity order, size, and shape particles”, WO/2007/024323 titled “Nanoparticle fabrication methods, systems, and materials” (Liquidia Technologies, Inc. and the University of North Carolina at Chapel Hill); WO/2010/009087 titled “Iontophoretic Delivery of a Controlled-Release Formulation in the Eye”, (Liquidia Technologies, Inc. and Eyegate Pharmaceuticals, Inc.) and WO/2009/132206 titled “Compositions and Methods for Intracellular Delivery and Release of Cargo”, WO/2007/133808 titled “Nano-particles for cosmetic applications”, WO/2007/056561 titled “Medical device, materials, and methods”, WO/2010/065748 titled “Method for producing patterned materials”, WO/2007/081876 titled “Nanostructured surfaces for biomedical/biomaterial applications and processes thereof” (Liquidia Technologies, Inc.). 
     Additional non-limiting examples of methods and devices for drug delivery to the eye include, for example, WO2011/106702 and U.S. Pat. No. 8,889,193 titled “Sustained delivery of therapeutic agents to an eye compartment”, WO2013/138343 and U.S. Pat. No. 8,962,577 titled “Controlled release formulations for the delivery of HIF-1 inhibitors”, WO/2013/138346 and US2013/0272994 titled “Non-Linear Multiblock Copolymer-Drug Conjugates for the Delivery of Active Agents”, WO2005/072710 and U.S. Pat. No. 8,957,034 titled “Drug and Gene Carrier Particles that Rapidly Move Through Mucus Barriers”, WO2008/030557, US2010/0215580, US2013/0164343 titled “Compositions and Methods for Enhancing Transport Through Mucous”, WO2012/061703, US2012/0121718, and US2013/0236556 titled “Compositions and Methods Relating to Reduced Mucoadhesion”, WO2012/039979 and US2013/0183244 titled “Rapid Diffusion of Large Polymeric Nanoparticles in the Mammalian Brain”, WO2012/109363 and US2013/0323313 titled “Mucus Penetrating Gene Carriers”, WO 2013/090804 and US2014/0329913 titled “Nanoparticles with enhanced mucosal penetration or decreased inflammation”, WO2013/110028 titled “Nanoparticle formulations with enhanced mucosal penetration”, WO2013/166498 and US2015/0086484 titled “Lipid-based drug carriers for rapid penetration through mucus linings” (The Johns Hopkins University); WO2013/166385 titled “Pharmaceutical Nanoparticles Showing Improved Mucosal Transport”, US2013/0323179 titled “Nanocrystals, Compositions, And Methods that Aid Particle Transport in Mucus” (The Johns Hopkins University and Kala Pharmaceuticals, Inc.); WO/2015/066444 titled “Compositions and methods for ophthalmic and/or other applications”, WO/2014/020210 and WO/2013/166408 titled “Pharmaceutical nanoparticles showing improved mucosal transport” (Kala Pharmaceuticals, Inc.); U.S. Pat. No. 9,022,970 titled “Ophthalmic injection device including dosage control device”, WO/2011/153349 titled “Ophthalmic compositions comprising pbo-peo-pbo block copolymers”, WO/2011/140203 titled “Stabilized ophthalmic galactomannan formulations”, WO/2011/068955 titled “Ophthalmic emulsion”, WO/2011/037908 titled “Injectable aqueous ophthalmic composition and method of use therefor”, US2007/0149593 titled “Pharmaceutical Formulation for Delivery of Receptor Tyrosine Kinase Inhibiting (RTKi) Compounds to the Eye”, U.S. Pat. No. 8,632,809 titled “Water insoluble polymer matrix for drug delivery” (Alcon, Inc.). 
     Additional non-limiting examples of drug delivery devices and methods include, for example, US20090203709 titled “Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor” (Abbott Laboratories); US20050009910 titled “Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of a prodrug”, US 20130071349 titled “Biodegradable polymers for lowering intraocular pressure”, U.S. Pat. No. 8,481,069 titled “Tyrosine kinase microspheres”, U.S. Pat. No. 8,465,778 titled “Method of making tyrosine kinase microspheres”, U.S. Pat. No. 8,409,607 titled “Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods”, U.S. Pat. No. 8,512,738 and US 2014/0031408 titled “Biodegradable intravitreal tyrosine kinase implants”, US 2014/0294986 titled “Microsphere Drug Delivery System for Sustained Intraocular Release”, U.S. Pat. No. 8,911,768 titled “Methods For Treating Retinopathy With Extended Therapeutic Effect” (Allergan, Inc.); U.S. Pat. No. 6,495,164 titled “Preparation of injectable suspensions having improved injectability” (Alkermes Controlled Therapeutics, Inc.); WO 2014/047439 titled “Biodegradable Microcapsules Containing Filling Material” (Akina, Inc.); WO 2010/132664 titled “Compositions And Methods For Drug Delivery” (Baxter International Inc. Baxter Healthcare SA); US20120052041 titled “Polymeric nanoparticles with enhanced drugloading and methods of use thereof” (The Brigham and Women&#39;s Hospital, Inc.); US20140178475, US20140248358, and US20140249158 titled “Therapeutic Nanoparticles Comprising a Therapeutic Agent and Methods of Making and Using Same” (BIND Therapeutics, Inc.); U.S. Pat. No. 5,869,103 titled “Polymer microparticles for drug delivery” (Danbiosyst UK Ltd.); U.S. Pat. No. 8,628,801 titled “Pegylated Nanoparticles” (Universidad de Navarra); US2014/0107025 titled “Ocular drug delivery system” (Jade Therapeutics, LLC); U.S. Pat. No. 6,287,588 titled “Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof”, U.S. Pat. No. 6,589,549 titled “Bioactive agent delivering system comprised of microparticles within a biodegradable to improve release profiles” (Macromed, Inc.); U.S. Pat. Nos. 6,007,845 and 5,578,325 titled “Nanoparticles and microparticles of non-linear hydrophilichydrophobic multiblock copolymers” (Massachusetts Institute of Technology); US20040234611, US20080305172, US20120269894, and US20130122064 titled “Ophthalmic depot formulations for periocular or subconjunctival administration (Novartis Ag); U.S. Pat. No. 6,413,539 titled “Block polymer” (Poly-Med, Inc.); US 20070071756 titled “Delivery of an agent to ameliorate inflammation” (Peyman); US 20080166411 titled “Injectable Depot Formulations And Methods For Providing Sustained Release Of Poorly Soluble Drugs Comprising Nanoparticles” (Pfizer, Inc.); U.S. Pat. No. 6,706,289 titled “Methods and compositions for enhanced delivery of bioactive molecules” (PR Pharmaceuticals, Inc.); and U.S. Pat. No. 8,663,674 titled “Microparticle containing matrices for drug delivery” (Surmodics). 
     IV. Uses of Active Compounds for Treatment of Selected Disorders 
     In one aspect, an effective amount of an active compound or its salt or composition as described herein is used to treat a medical disorder which is an inflammatory or immune condition, a disorder mediated by the complement cascade (including a dysfunctional cascade) including a complement D-related disorder, a disorder or abnormality of a cell that adversely affects the ability of the cell to engage in or respond to normal complement activity, or an undesired complement-mediated response to a medical treatment, such as surgery or other medical procedure or a pharmaceutical or biopharmaceutical drug administration, a blood transfusion, or other allogenic tissue or fluid administration. 
     In one embodiment, the disorder is selected from fatty liver and conditions stemming from fatty liver, such as nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis and liver failure. In one embodiment of the present invention, a method is provided for treating fatty liver disease in a host by administering an effective amount of an active compound or its salt or composition as described herein. 
     In another embodiment, an active compound or its salt or composition as described herein is used to modulate an immune response prior to or during surgery or other medical procedure. One non-limiting example is use in connection with acute or chronic graft versus host disease, which is a common complication as a result of allogeneic tissue transplant, and can also occur as a result of a blood transfusion. 
     In one embodiment, the present invention provides a method of treating or preventing dermatomyositis by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein. 
     In one embodiment, the present invention provides a method of treating or preventing amyotrophic lateral sclerosis by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein. 
     In another embodiment, a method is provided for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceutical or biotherapeutic (e.g. CAR T-cell therapy or monoclonal antibody therapy) in a host by administering an effective amount of an active compound or its salt or composition as described herein. Various types of cytokine or inflammatory reactions may occur in response to a number of factors, such as the administrations of biotherapeutics. In one embodiment, the cytokine or inflammatory reaction is cytokine release syndrome. In one embodiment, the cytokine or inflammatory reaction is tumor lysis syndrome (which also leads to cytokine release). Symptoms of cytokine release syndrome range from fever, headache, and skin rashes to bronchospasm, hypotension and even cardiac arrest. Severe cytokine release syndrome is described as cytokine storm, and can be fatal. 
     Fatal cytokine storms have been observed in response to infusion with several monoclonal antibody therapeutics. See, Abramowicz D, et al. “Release of tumor necrosis factor, interleukin-2, and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients”  Transplantation  (1989) 47(4):606-8; Chatenoud L, et al. “In vivo cell activation following OKT3 administration. Systemic cytokine release and modulation by corticosteroids”  Transplantation  (1990) 49(4):697-702; and Lim L C, Koh L P, and Tan P. “Fatal cytokine release syndrome with chimeric anti-CD20 monoclonal antibody rituximab in a 71-year-old patient with chronic lymphocytic leukemia”  J. Clin Oncol . (1999) 17(6):1962-3. 
     Also contemplated herein, is the use of an active compound or its salt or composition as described herein to mediate an adverse immune response in patients receiving bi-specific T-cell engagers (BiTE). A bi-specific T-cell engager directs T-cells to target and bind with a specific antigen on the surface of a cancer cell. For example, Blinatumomab (Amgen), a BiTE has recently been approved as a second line therapy in Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia. Blinatumomab is given by continuous intravenous infusion in 4-week cycles. The use of BiTE agents has been associated with adverse immune responses, including cytokine release syndrome. The most significantly elevated cytokines in the CRS associated with ACT include IL-10, IL-6, and IFN-γ (Klinger et al., Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood (2012) 119:6226-6233). 
     In another embodiment, the disorder is episcleritis, idiopathic episcleritis, anterior episcleritis, or posterior episcleritis. In one embodiment, the disorder is idiopathic anterior uveitis, HLA-B27 related uveitis, herpetic keratouveitis, Posner Schlossman syndrome, Fuch&#39;s heterochromic iridocyclitis, or cytomegalovirus anterior uveitis. 
     In yet another embodiment, the disorder is selected from:
     (i) vitritis, sarcoidosis, syphilis, tuberculosis, or Lyme disease;   (ii) retinal vasculitis, Eales disease, tuberculosis, syphilis, or toxoplasmosis;   (iii) neuroretinitis, viral retinitis, or acute retinal necrosis;   (iv) varicella zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, lichen planus, or Dengue-associated disease (e.g., hemorraghic Dengue Fever);   (v) Masquerade syndrome, contact dermatitis, trauma induced inflammation, UVB induced inflammation, eczema, granuloma annulare, or acne.   

     In an additional embodiment, the disorder is selected from:
     (i) acute myocardial infarction, aneurysm, cardiopulmonary bypass, dilated cardiomyopathy, complement activation during cardiopulmonary bypass operations, coronary artery disease, restenosis following stent placement, or percutaneous transluminal coronary angioplasty (PTCA);   (ii) antibody-mediated transplant rejection, anaphylactic shock, anaphylaxis, allogenic transplant, humoral and vascular transplant rejection, graft dysfunction, graft-versus-host disease, Graves&#39; disease, adverse drug reactions, or chronic graft vasculopathy; (iii) allergic bronchopulmonary aspergillosis, allergic neuritis, drug allergy, radiation-induced lung injury, eosinophilic pneumonia, radiographic contrast media allergy, bronchiolitis obliterans, or interstitial pneumonia;   (iv) amyotrophic lateral sclerosis, parkinsonism-dementia complex, sporadic frontotemporal dementia, frontotemporal dementia with Parkinsonism linked to chromosome 17, frontotemporal lobar degeneration, tangle only dementia, cerebral amyloid angiopathy, cerebrovascular disorder, certain forms of frontotemporal dementia, chronic traumatic encephalopathy (CTE), PD with dementia (PDD), argyrophilic grain dementia, dementia pugilistica, dementia with Lewy Bodies (DLB), or multi-infarct dementia;   (v) Creutzfeldt-Jakob disease, Huntington&#39;s disease, multifocal motor neuropathy (MMN), prion protein cerebral amyloid angiopathy, polymyositis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, non-Guamanian motor neuron disease with neurofibrillary tangles, neural regeneration, or diffuse neurofibrillary tangles with calcification.   

     In one embodiment, the disorder is selected from:
     (i) atopic dermatitis, dermatitis, dermatomyositis, dermatomyositis bullous pemphigoid, scleroderma, sclerodermatomyositis, psoriatic arthritis, pemphigus vulgaris, Discoid lupus erythematosus, cutaneous lupus, chilblain lupus erythematosus, or lupus erythematosus-lichen planus overlap syndrome;   (ii) cryoglobulinemic vasculitis, mesenteric/enteric vascular disorder, peripheral vascular disorder, antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), IL-2 induced vascular leakage syndrome, or immune complex vasculitis;   (iii) angioedema, low platelets (HELLP) syndrome, sickle cell disease, platelet refractoriness, red cell casts, or typical or infectious hemolytic uremic syndrome (tHUS);   (iv) hematuria, hemodialysis, hemolysis, hemorrhagic shock, immunothrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), idiopathic thrombocytopenic purpura (ITP), drug-induced thrombocytopenia, autoimmune hemolytic anemia (AIHA), azotemia, blood vessel and/or lymph vessel inflammation, rotational atherectomy, or delayed hemolytic transfusion reaction;   (v) British type amyloid angiopathy, Buerger&#39;s disease, bullous pemphigoid, Clq nephropathy, cancer, or catastrophic antiphospholipid syndrome.   

     In another embodiment, the disorder is selected from:
     (i) wet AMD, dry AMD, chorioretinal degeneration, choroidal neovascularization (CNV), choroiditis, loss of RPE function, loss of vision (including loss of visual acuity or visual field), loss of vision from AMD, retinal damage in response to light exposure, retinal degeneration, retinal detachment, retinal dysfunction, retinal neovascularization (RNV), retinopathy of prematurity, or RPE degeneration;   (ii) pseudophakic bullous keratopathy, symptomatic macular degeneration related disorder, optic nerve degeneration, photoreceptor degeneration, cone degeneration, loss of photoreceptor cells, pars planitis, scleritis, proliferative vitreoretinopathy, or formation of ocular drusen;   (iii) chronic urticaria, Churg-Strauss syndrome, cold agglutinin disease (CAD), corticobasal degeneration (CBD), cryoglobulinemia, cyclitis, damage of the Bruch&#39;s membrane, Degos disease, diabetic angiopathy, elevated liver enzymes, endotoxemia, epidermolysis bullosa, or epidermolysis bullosa acquisita;   (iv) essential mixed cryoglobulinemia, excessive blood urea nitrogen-BUN, focal segmental glomerulosclerosis, Gerstmann-Straussler-Scheinker disease, giant cell arteritis, gout, Hallervorden-Spatz disease, Hashimoto&#39;s thyroiditis, Henoch-Schonlein purpura nephritis, or abnormal urinary sediments;   (v) hepatitis, hepatitis A, hepatitis B, hepatitis C or human immunodeficiency virus (HIV),   (vi) a viral infection more generally, for example selected from Flaviviridae, Retroviruses, Coronaviridae, Poxviridae, Adenoviridae, Herpesviridae, Caliciviridae, Reoviridae, Picornaviridae, Togaviridae, Orthomyxoviridae, Rhabdoviridae, or Hepadnaviridae;   (vii)  Neisseria meningitidis , shiga toxin  E. coli -related hemolytic uremic syndrome (STEC-HUS),  Streptococcus , or poststreptococcal glomerulonephritis.   

     In a further embodiment, the disorder is selected from:
     (viii) hyperlipidemia, hypertension, hypoalbuminemia, hypobolemic shock, hypocomplementemic urticarial vasculitis syndrome, hypophosphastasis, hypovolemic shock, idiopathic pneumonia syndrome, or idiopathic pulmonary fibrosis;   (ix) inclusion body myositis, intestinal ischemia, iridocyclitis, iritis, juvenile chronic arthritis, Kawasaki&#39;s disease (arteritis), or lipiduria;   (x) membranoproliferative glomerulonephritis (MPGN) I, microscopic polyangiitis, mixed cryoglobulinemia, molybdenum cofactor deficiency (MoCD) type A, pancreatitis, panniculitis, Pick&#39;s disease, polyarteritis nodosa (PAN), progressive subcortical gliosis, proteinuria, reduced glomerular filtration rate (GFR), or renovascular disorder;   (xi) multiple organ failure, multiple system atrophy (MSA), myotonic dystrophy, Niemann-Pick disease type C, chronic demyelinating diseases, or progressive supranuclear palsy;   (xii) spinal cord injury, spinal muscular atrophy, spondyloarthropathies, Reiter&#39;s syndrome, spontaneous fetal loss, recurrent fetal loss, pre-eclampsia, synucleinopathy, Takayasu&#39;s arteritis, post-partum thryoiditis, thyroiditis, Type I cryoglobulinemia, Type II mixed cryoglobulinemia, Type III mixed cryoglobulinemia, ulcerative colitis, uremia, urticaria, venous gas embolus (VGE), or Wegener&#39;s granulomatosis;   

     In one embodiment, an active compound or its salt or composition as described herein is useful for treating or preventing a disorder selected from autoimmune oophoritis, endometriosis, autoimmune orchitis, Ord&#39;s thyroiditis, autoimmune enteropathy, coeliac disease, Hashimoto&#39;s encephalopathy, antiphospholipid syndrome (APLS) (Hughes syndrome), aplastic anemia, autoimmune lymphoproliferative syndrome (Canale-Smith syndrome), autoimmune neutropenia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, adipose dolorosa (Dercum&#39;s disease), adult onset Still&#39;s disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, eosinophilic fasciitis (Shulman&#39;s syndrome), Felty syndrome, IgG4-related disease, mixed connective tissue disease (MCTD), palindromic rheumatism (Hench-Rosenberg syndrome), Parry-Romberg syndrome, Parsonage-Turner syndrome, relapsing polychondritis (Meyenburg-Altherr-Uehlinger syndrome), retroperitonial fibrosis, rheumatic fever, Schnitzler syndrome, fibromyalgia, neuromyotonia (Isaac&#39;s disease), paraneoplastic degeneration, autoimmune inner ear disease, Meniere&#39;s disease, interstitial cystitis, autoimmune pancreatitis, zika virus-related disorders, chikungunya virus-related disorders, subacute bacterial endocarditis (SBE), IgA nephropathy, IgA vasculitis, polymyalgia rheumatic, rheumatoid vasculitis, alopecia areata, autoimmune progesterone dermatitis, dermatitis herpetiformis, erythema nodosum, gestational pemphigoid, hidradenitis suppurativa, lichen sclerosus, linear IgA disease (LAD), morphea, myositis, pityriasis lichenoides et varioliformis acuta, vitiligo post-myocardial infarction syndrome (Dressler&#39;s syndrome), post-pericardiotomy syndrome, autoimmune retinopathy, Cogan syndrome, Graves opthalmopathy, ligneous conjunctivitis, Mooren&#39;s ulcer, opsoclonus myoclonus syndrome, optic neuritis, retinocochleocerebral vasculopathy (Susac&#39;s syndrome), sympathetic opthalmia, Tolosa-Hunt syndrome, interstitial lung disease, antisynthetase syndrome, Addison&#39;s disease, autoimmune polyendocrine syndrome (APS) type I, autoimmune polyendocrine syndrome (APS) type II, autoimmune polyendocrine syndrome (APS) type III, disseminated sclerosis (multiple sclerosis, pattern II), rapidly progressing glomerulonephritis (RPGN), juvenile rheumatoid arthritis, enthesitis-related arthritis, reactive arthritis (Reiter&#39;s syndrome), autoimmune hepatitis or lupoid hepatitis, primary biliary cirrhosis (PBS), primary sclerosing cholangitis, microscopic colitis, latent lupus (undifferentiated connective tissue disease (UCTD)), acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-n-methyl-D-aspartate receptor encephalitis, Balo concentric sclerosis (Schilders disease), Bickerstaff&#39;s encephalitis, chronic inflammatory demyelinating polyneuropathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton mysathenic syndrome, Oshtoran syndrome, pediatric autoimmune neuropsychiatric disorder associated with  Streptococcus  (PANDAS), progressive inflammatory neuropathy, restless leg syndrome, stiff person syndrome, Sydenhem syndrome, transverse myelitis, lupus vasculitis, leukocytoclastic vasculitis, Microscopic Polyangiitis, polymyositis or ischemic-reperfusion injury of the eye. 
     In one embodiment, an active compound or its salt or composition as described herein is useful for treating or preventing a disorder that is mediated by the complement pathway, and in particular, a pathway that is modulated by complement Factor D. In another embodiment, the compound is effective to treat the disorder, albeit through a different mechanism. 
     In certain embodiments, the disorder is an inflammatory disorder, an immune disorder, an autoimmune disorder, or complement Factor D related disorders in a host. In one embodiment, the disorder is an ocular disorder or an eye disorder. 
     Examples of eye disorders that may be treated according to the compositions and methods disclosed herein include amoebic keratitis, fungal keratitis, bacterial keratitis, viral keratitis, onchorcercal keratitis, bacterial keratoconjunctivitis, viral keratoconjunctivitis, corneal dystrophic diseases, Fuchs&#39; endothelial dystrophy, Sjogren&#39;s syndrome, Stevens-Johnson syndrome, autoimmune dry eye diseases, environmental dry eye diseases, corneal neovascularization diseases, post-corneal transplant rejection prophylaxis and treatment, autoimmune uveitis, infectious uveitis, anterior uveitis, posterior uveitis (including toxoplasmosis), pan-uveitis, an inflammatory disease of the vitreous or retina, endophthalmitis prophylaxis and treatment, macular edema, macular degeneration, age related macular degeneration, proliferative and non-proliferative diabetic retinopathy, hypertensive retinopathy, an autoimmune disease of the retina, primary and metastatic intraocular melanoma, other intraocular metastatic tumors, open angle glaucoma, closed angle glaucoma, pigmentary glaucoma and combinations thereof. 
     In a further embodiment, the disorder is selected from age-related macular degeneration, glaucoma, diabetic retinopathy, neuromyelitis optica (NMO), vasculitis, hemodialysis, blistering cutaneous diseases (including bullous pemphigoid, pemphigus, and epidermolysis bullosa), ocular cicatrical pemphigoid, uveitis, adult macular degeneration, diabetic retinopa retinitis pigmentosa, macular edema, Behcet&#39;s uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, postoperative inflammation, and retinal vein occlusion, or uveitis (including Behcet&#39;s disease and other sub-types of uveitis). 
     In some embodiments, complement mediated diseases include ophthalmic diseases (including early or neovascular age-related macular degeneration and geographic atrophy), autoimmune diseases (including arthritis, rheumatoid arthritis), respiratory diseases, cardiovascular diseases. In other embodiments, the compounds of the invention are suitable for use in the treatment of diseases and disorders associated with fatty acid metabolism, including obesity and other metabolic disorders. 
     Disorders that may be treated or prevented by an active compound or its salt or composition as described herein also include, but are not limited to:
     (i) paroxysmal nocturnal hemoglobinuria (PNH), hereditary angioedema, capillary leak syndrome, atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, or hemodialysis;   (ii) myasthenia gravis, multiple sclerosis, C3 glomerulonephritis (C3GNs), MPGN II (dense deposit disease), neurological disorders, Guillain Barre Syndrome, diseases of the central nervous system and other neurodegenerative conditions, glomerulonephritis (including membrane proliferative glomerulonephritis), SLE nephritis, proliferative nephritis, liver fibrosis, tissue regeneration and neural regeneration, or Barraquer-Simons Syndrome;   (iii) inflammatory effects of sepsis, systemic inflammatory response syndrome (SIRS), disorders of inappropriate or undesirable complement activation, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, system lupus erythematosus (SLE), Crohn&#39;s disease, rheumatoid arthritis, inflammatory bowel disease, lupus nephritides, arthritis, immune complex disorders and autoimmune diseases, systemic lupus, or lupus erythematosus;   (iv) ischemia/reperfusion injury (FR injury), myocardial infarction, myocarditis, post-ischemic reperfusion conditions, balloon angioplasty, atherosclerosis, post-pump syndrome in cardiopulmonary bypass or renal bypass, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, antiphospholipid syndrome, autoimmune heart disease, ischemia-reperfusion injuries, obesity, or diabetes;   (v) Alzheimer&#39;s dementia, stroke, schizophrenia, traumatic brain injury, trauma, Parkinson&#39;s disease, epilepsy, transplant rejection, prevention of fetal loss, biomaterial reactions (e.g. in hemodialysis, inplants), hyperacute allograft rejection, xenograft rejection, transplantation, psoriasis, burn injury, thermal injury including burns or frostbite;   (vi) asthma, allergy, acute respiratory distress syndrome (ARDS), cystic fibrosis, adult respiratory distress syndrome, dyspnea, hemoptysis, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, inert dusts and minerals (e.g., silicon, coal dust, beryllium, and asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (due to irritant gases and chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), smoke injury, thermal injury (e.g., burn, freeze), bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture&#39;s Syndrome (anti-glomerular basement membrane nephritis), pulmonary vasculitis, Pauci-immune vasculitis, or immune complex-associated inflammation.   

     In one embodiment, a method for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in a host is provided that includes the administration of an effective amount of an active compound or its salt or composition as described herein. In another embodiment, a method for the treatment of age-related macular degeneration (AMD) in a host is provided that includes the administration of an effective amount an active compound or its salt or composition as described herein. In another embodiment, a method for the treatment of rheumatoid arthritis in a host is provided that includes the administration of an effective amount of an active compound or its salt or composition as described herein. In another embodiment, a method for the treatment of multiple sclerosis in a host is provided that includes the administration of an effective amount of an active compound or its salt or composition as described herein. In another embodiment, a method for the treatment of myasthenia gravis in a host is provided that includes the administration of an effective amount of an active compound or its salt or composition as described herein. In another embodiment, a method for the treatment of atypical hemolytic uremic syndrome (aHUS) in a host is provided that includes the administration of an effective amount of an active compound or its salt or composition as described herein. In another embodiment, a method for the treatment of C3 glomerulonephritis in host is provided that includes the administration of an effective amount of an active compound or its salt or composition as described herein. In another embodiment, a method for the treatment of abdominal aortic aneurysm in host is provided that includes the administration of an effective amount of an active compound or its salt or composition as described herein. In another embodiment, a method for the treatment of neuromyelitis optica (NMO) in a host is provided that includes the administration of an effective amount of an active compound or its salt or composition as described herein. 
     In one embodiment, a method for the treatment of sickle cell in a host is provided that includes the administration of an effective amount of an active compound or its salt or composition as described herein. In one embodiment, a method for the treatment of immunothrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), or idiopathic thrombocytopenic purpura (ITP) in a host is provided that includes the administration of an effective amount of an active compound or its salt or composition as described herein. In one embodiment, a method for the treatment of ANCA-vasculitis in a host is provided that includes the administration of an effective amount of an active compound or its salt or composition as described herein. In one embodiment, a method for the treatment of IgA nephropathy in a host is provided that includes the administration of an effective amount of an active compound or its salt or composition as described herein. In one embodiment, a method for the treatment of rapidly progressing glomerulonephritis (RPGN), in a host is provided that includes the administration of an effective amount of an active compound or its salt or composition as described herein. In one embodiment, a method for the treatment of lupus nephritis, in a host is provided that includes the administration of an effective amount of an active compound or its salt or composition as described herein. In one embodiment, a method for the treatment of hemorraghic dengue fever, in a host is provided that includes the administration of an effective amount of an active compound or its salt or composition as described herein. 
     In some embodiments, the present invention provides methods of treating or preventing an inflammatory disorder or a complement related disease, by administering to a host in need thereof an effective amount of an active compound or its salt or composition as described herein. In some embodiments, the present invention provides methods of treating or preventing an inflammatory disorder more generally, an immune disorder, autoimmune disorder, or complement Factor D related disease in a host, by providing an effective amount of a compound or pharmaceutically acceptable salt of an active compound or its salt or composition as described herein to patient with a Factor D mediated inflammatory disorder. An active compound or its salt or composition as described herein as the only active agent or may be provided together with one or more additional active agents. 
     In one embodiment, a method for the treatment of a disorder associated with a dysfunction in the complement cascade in a host is provided that includes the administration of an effective amount of an active compound or its salt or composition as described herein. In one embodiment, a method of inhibiting activation of the alternative complement pathway in a subject is provided that includes the administration of an effective amount of an active compound or its salt or composition as described herein. In one embodiment, a method of modulating Factor D activity in a subject is provided that includes the administration of an effective amount of an active compound or its salt or composition as described herein. 
     In an additional alternative embodiment, an active compound or its salt or composition as described herein is used in the treatment of an autoimmune disorder. 
     The complement pathway enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells from the body. It is part of the innate immune system and in healthy individuals is an essential process. Inhibiting the complement pathway will decrease the body&#39;s immune system response. Therefore, it is an object of the present invention to treat autoimmune disorders by administering an effective does of an active compound or its salt or composition as described herein to a subject in need thereof. 
     In one embodiment the autoimmune disorder is caused by activity of the complement system. In one embodiment the autoimmune disorder is caused by activity of the alternative complement pathway. In one embodiment the autoimmune disorder is caused by activity of the classical complement pathway. In another embodiment the autoimmune disorder is caused by a mechanism of action that is not directly related to the complement system, such as the over-proliferation of T-lymphocytes or the over-production of cytokines. 
     Non-limiting examples of autoimmune disorders include: lupus, allograft rejection, autoimmune thyroid diseases (such as Graves&#39; disease and Hashimoto&#39;s thyroiditis), autoimmune uveoretinitis, giant cell arteritis, inflammatory bowel diseases (including Crohn&#39;s disease, ulcerative colitis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, and terminal ileitis), diabetes, multiple sclerosis, pernicious anemia, psoriasis, rheumatoid arthritis, sarcoidosis, and scleroderma. 
     In one embodiment, an active compound or its salt or composition as described herein is used in the treatment of lupus. Non-limiting examples of lupus include lupus erythematosus, cutaneous lupus, discoid lupus erythematosus, chilblain lupus erythematosus, or lupus erythematosus-lichen planus overlap syndrome. 
     Lupus erythematosus is a general category of disease that includes both systemic and cutaneous disorders. The systemic form of the disease can have cutaneous as well as systemic manifestations. However, there are also forms of the disease that are only cutaneous without systemic involvement. For example, SLE is an inflammatory disorder of unknown etiology that occurs predominantly in women, and is characterized by articular symptoms, butterfly erythema, recurrent pleurisy, pericarditis, generalized adenopathy, splenomegaly, as well as CNS involvement and progressive renal failure. The sera of most patients (over 98%) contain antinuclear antibodies, including anti-DNA antibodies. High titers of anti-DNA antibodies are essentially specific for SLE. Conventional treatment for this disease has been the administration of corticosteroids or immunosuppressants. 
     There are three forms of cutaneous lupus: chronic cutaneous lupus (also known as discoid lupus erythematosus or DLE), subacute cutaneous lupus, and acute cutaneous lupus. DLE is a disfiguring chronic disorder primarily affecting the skin with sharply circumscribed macules and plaques that display erythema, follicular plugging, scales, telangiectasia and atrophy. The condition is often precipitated by sun exposure, and the early lesions are erythematous, round scaling papules that are 5 to 10 mm in diameter and display follicular plugging. DLE lesions appear most commonly on the cheeks, nose, scalp, and ears, but they may also be generalized over the upper portion of the trunk, extensor surfaces of the extremities, and on the mucous membranes of the mouth. If left untreated, the central lesion atrophies and leaves a scar. Unlike SLE, antibodies against double-stranded DNA (e.g., DNA-binding test) are almost invariably absent in DLE. 
     Multiple Sclerosis is an autoimmune demyelinating disorder that is believed to be T lymphocyte dependent. MS generally exhibits a relapsing-remitting course or a chronic progressive course. The etiology of MS is unknown, however, viral infections, genetic predisposition, environment, and autoimmunity all appear to contribute to the disorder. Lesions in MS patients contain infiltrates of predominantly T lymphocyte mediated microglial cells and infiltrating macrophages. CD4+ T lymphocytes are the predominant cell type present at these lesions. The hallmark of the MS lesion is plaque, an area of demyelination sharply demarcated from the usual white matter seen in Mill scans. Histological appearance of MS plaques varies with different stages of the disease. In active lesions, the blood-brain barrier is damaged, thereby permitting extravasation of serum proteins into extracellular spaces. Inflammatory cells can be seen in perivascular cuffs and throughout white matter. CD4+ T-cells, especially Th1, accumulate around postcapillary venules at the edge of the plaque and are also scattered in the white matter. In active lesions, up-regulation of adhesion molecules and markers of lymphocyte and monocyte activation, such as IL2-R and CD26 have also been observed. Demyelination in active lesions is not accompanied by destruction of oligodendrocytes. In contrast, during chronic phases of the disease, lesions are characterized by a loss of oligodendrocytes and hence, the presence of myelin oligodendrocyte glycoprotein (MOG) antibodies in the blood. 
     Diabetes can refer to either type 1 or type 2 diabetes. In one embodiment an active compound or its salt or composition as described herein is provided at an effective dose to treat a patient with type 1 diabetes. In one embodiment an active compound or its salt or composition as described herein is provided at an effective dose to treat a patient with type 2 diabetes. 
     Type 1 diabetes is an autoimmune disease. An autoimmune disease results when the body&#39;s system for fighting infection (the immune system) turns against a part of the body. The pancreas then produces little or no insulin. 
     V. Combination Therapy 
     In one embodiment an active compound or its salt or composition as described herein may be provided in combination or alternation with or preceded by, concomitant with or followed by, an effective amount of at least one additional therapeutic agent, for example, for treatment of a disorder listed herein. Non-limiting examples of second active agents for such combination therapy are provided below. 
     In one embodiment, an active compound or its salt or composition as described herein may be provided in combination or alternation with at least one additional inhibitor of the complement system or a second active compound with a different biological mechanism of action. In the description below and herein generally, whenever any of the terms referring to an active compound or its salt or composition as described herein are used, it should be understood that pharmaceutically acceptable salts, prodrugs or compositions are considered included, unless otherwise stated or inconsistent with the text. 
     In non-limiting embodiments, an active compound or its salt or composition as described herein may be provided together with a protease inhibitor, a soluble complement regulator, a therapeutic antibody (monoclonal or polyclonal), complement component inhibitor, receptor agonist, or siRNA. 
     In other embodiments, an active compound described herein is administered in combination or alternation with an antibody against tumor necrosis factor (TNF), including but not limited to infliximab (Remicade), adalimumab, certolizumab, golimumab, or a receptor fusion protein such as etanercept (Embrel). 
     In another embodiment, an active compound as described herein can be administered in combination or alternation with an anti-CD20 antibody, including but not limited to rituximab (Rituxan), adalimumab (Humira), ofatumumab (Arzerra), tositumomab (Bexxar), obinutuzumab (Gazyva), or ibritumomab (Zevalin). 
     In an alternative embodiment, an active compound as described herein can be administered in combination or alternation with an anti-IL6 antibody, including but not limited to tocilizumab (Actemra) and siltuximab (Sylvant). 
     In an alternative embodiment, an active compound as described herein can be administered in combination or alternation with an IL17 inhibitor, including but not limited to secukibumab (Cosentyx). 
     In an alternative embodiment, an active compound as described herein can be administered in combination or alternation with a p40 (IL12/IL23) inhibitor, including but not limited to ustekinumab (Stelara). 
     In an alternative embodiment, an active compound as described herein can be administered in combination or alteration with an IL23 inhibitor, including but not limited to risankizumab. 
     In an alternative embodiment, an active compound as described herein can be administered in combination or alteration with an anti-interferon α antibody, for example but not limited to sifalimumab. 
     In an alternative embodiment, an active compound as described herein can be administered in combination or alteration with a kinase inhibitor, for example but not limited to a JAK1/JAK3 inhibitor, for example but not limited to tofacitinib (Xelianz). In an alternative embodiment, an active compound as described herein can be administered in combination or alteration with a JAK1/JAK2 inhibitor, for example but not limited to baracitibib. 
     In another embodiment, an active compound as described herein can be administered in combination or alternation with an immune checkpoint inhibitor. Non-limiting examples of checkpoint inhibitors are anti-PD-1 or anti-PDL1 antibodies (for example, Nivolumab, Pembrolizumab, Pidilizumab and Atezolizumab) and anti-CTLA4 antibodies (Ipilimumab and Tremelimumab). 
     Non-limiting examples of active agents that can be used in combination with active compounds described herein are: 
     Protease inhibitors: plasma-derived C1-INH concentrates, for example Cetor (Sanquin), Berinert-P® (CSL Behring, Lev Pharma), and Cinryze; recombinant human C1-inhibitors, for example Rhucin; ritonavir (Norvir, Abbvie, Inc.); 
     Soluble complement regulators: Soluble complement receptor 1 (TP10) (Avant Immunotherapeutics); sCR1-sLe x /TP-20 (Avant Immunotherapeutics); MLN-2222/CAB-2 (Millenium Pharmaceuticals); Mirococept (Inflazyme Pharmaceuticals); 
     Therapeutic antibodies: Eculizumab/Soliris (Alexion Pharmaceuticals); Pexelizumab (Alexion Pharmaceuticals); Ofatumumab (Genmab A/S); TNX-234 (Tanox); TNX-558 (Tanox); TA106 (Taligen Therapeutics); Neutrazumab (G2 Therapies); Anti-properdin (Novelmed Therapeutics); HuMax-CD38 (Genmab A/S); 
     Complement component inhibitors: Compstatin/POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix); 
     Receptor agonists: PMX-53 (Peptech Ltd.); JPE-137 (Jerini); JSM-7717 (Jerini); 
     Others: Recombinant human MBL (rhMBL; Enzon Pharmaceuticals); 
     Imides and glutarimide derivatives such as thalidomide, lenalidomide, pomalidomide; 
     Additional non-limiting examples that can be used in combination or alternation with an active compound or its salt or composition as described herein include the following. 
     
       
         
           
               
            
               
                   
               
               
                 Non-limiting examples of potential therapeutics for combination therapy 
               
            
           
           
               
               
               
               
            
               
                 Name 
                 Target 
                 Company 
                 Class of Molecule 
               
               
                   
               
               
                 LFG316 
                 C5 
                 Novartis/Morphosys 
                 Monoclonal antibody 
               
               
                 4 (1MEW) APL-1,  
                 C3/C3b 
                 Apella 
                 Compstatin Family 
               
               
                 APL-2 
                   
                   
                   
               
               
                 4 (1MeW) POT-4 
                 C3/C3b 
                 Potentia 
                 Compstatin Family 
               
               
                 Anti-C5 siRNA 
                 C5 
                 Alnylam 
                 Si-RNA 
               
               
                 Anti-FB siRNA 
                 CFB 
                 Alnylam 
                 SiRNA 
               
               
                 ARC1005 
                 C5 
                 Novo Nordisk 
                 Aptamers 
               
               
                 ATA 
                 C5 
                 N.A. 
                 Chemical 
               
               
                 Coversin 
                 C5 
                 Volution Immuno- 
                 Small animal protein 
               
               
                   
                   
                 Pharmaceuticals 
                   
               
               
                 CP40/AMY-101,  
                 C3/C3b 
                 Amyndas 
                 Compstatin Family 
               
               
                 PEG-Cp40 
                   
                   
                   
               
               
                 CRIg/CFH 
                 CAP C3 
                 NA 
                 CFH-based protein 
               
               
                   
                 convertase 
                   
                   
               
               
                 Cynryze 
                 C1n/C1s 
                 ViroPharma/Baxter 
                 Human purified protein 
               
               
                 FCFD4514S 
                 CFD 
                 Genentech/Roche 
                 Monoclonal antibody 
               
               
                 H17 
                 C3 
                 EluSys Therapeutics 
                 Monoclonal antibody 
               
               
                   
                 (C3b/iC3b) 
                   
                   
               
               
                 Mini-CFH 
                 CAP C3 
                 Amyndas 
                 CFH-based protein 
               
               
                   
                 convertase 
                   
                   
               
               
                 Mirococept (APT070) 
                 CAP and CCP 
                 NA 
                 CR1-based protein 
               
               
                   
                 C3 
                   
                   
               
               
                 Mubodine 
                 C5 
                 Adienne 
                 Monoclonal antibody 
               
               
                 RA101348 
                 C5 
                 Rapharma 
                 Small molecule 
               
               
                 sCR1 (CDX-1135) 
                 CAP and CP 
                 Celldex 
                 CR1-based protein 
               
               
                   
                 C3 
                   
                   
               
               
                 SOBI002 
                 C5 
                 Swedish Orphan 
                 Affibody 
               
               
                   
                   
                 Biovitrum 
                   
               
               
                 SOMAmers 
                 C5 
                 SomaLogic 
                 Aptamers 
               
               
                 SOMAmers 
                 CFB and CFD 
                 SomaLogic 
                 Aptamers (SELEX) 
               
               
                 TA106 
                 CFB 
                 Alexion 
                 Monoclonal antibody 
               
               
                   
                   
                 Pharmaceuticals 
                   
               
               
                 TNT003 
                 C1s 
                 True North 
                 Monoclonal antibody 
               
               
                 TT30 (CR2/CFH) 
                 CAP C3 
                 Alexion 
                 CFH-based protein 
               
               
                   
                 convertase 
                   
                   
               
               
                 TT32 (CR2/CR1) 
                 CAP and CCP 
                 Alexion 
                 CR1-based protein 
               
               
                   
                 C3 
                 Pharmaceuticals 
                   
               
               
                 Nafamostat (FUT-175, 
                 C1s, CFD, 
                 Torri Pharmaceuticals 
                 Small molecule 
               
               
                 Futhan) 
                 other proteases 
                   
                   
               
               
                 OMS721 
                 MASP-2 
                 Omeros 
                 Monoclonal antibody 
               
               
                 OMS906 
                 MASP-2 
                 Omeros 
                 Monoclonal antibody 
               
               
                 Bikaciomab, NM9308 
                 CFB 
                 Novelmed 
                 Monoclonal antibody 
               
               
                 NM9401 
                 Properdin 
                 Novelmed 
                 Monoclonal antibody 
               
               
                 CVF, HC-1496 
                 C3 
                 InCode 
                 Recombinant peptide 
               
               
                 ALXN1102/ALXN1103 
                 C3-conv, C3b 
                 Alexion 
                 Regulator 
               
               
                 (TT30) 
                   
                 Pharmaceuticals 
                   
               
               
                 rFH 
                 C3-conv, C3b 
                 Optherion 
                 Regulator 
               
               
                 5C6, AMY-301 
                 CFH 
                 Amyndas 
                 Regulator 
               
               
                 Erdigna 
                 C5 
                 Adienne Pharma 
                 Antibody 
               
               
                 ARC1905 
                 C5 
                 Opthotech 
                 Monoclonal Antibody 
               
               
                 MEDI7814 
                 C5/C5a 
                 MedImmune 
                 Monoclonal Antibody 
               
               
                 NOX-D19 
                 C5a 
                 Noxxon 
                 Aptamer (Spiegelmer) 
               
               
                 IFX-1, CaCP29 
                 C5a 
                 InflaRx 
                 Monoclonal Antibody 
               
               
                 PMX53, PMX205 
                 C5aR 
                 Cephalon, Teva 
                 Peptidomimetic 
               
               
                 CCX168 
                 C5aR 
                 ChemoCentryx 
                 Small molecule 
               
               
                 ADC-1004 
                 C5aR 
                 A1ligator Bioscience 
                 Small molecule 
               
               
                 Anti-C5aR-151, 
                 C5aR 
                 Novo Nordisk 
                 Monoclonal Antibody 
               
               
                 NN8209; Anti-C5aR- 
                   
                   
                   
               
               
                 215, NN8210 
                   
                   
                   
               
               
                 Imprime PGG 
                 CR3 
                 Biothera 
                 Soluble beta-glucan 
               
               
                   
               
            
           
         
       
     
     In one embodiment, an active compound or its salt or composition as described herein may be provided together with a compound that inhibits an enzyme that metabolizes an administered protease inhibitor. In one embodiment, a compound or salt may be provided together with ritonavir. 
     In one embodiment, an active compound or its salt or composition as described herein may be provided in combination with a complement C5 inhibitor or C5 convertase inhibitor. In another embodiment, an active compound or its salt or composition as described herein may be provided in combination with eculizumab, a monoclonal antibody directed to the complement factor C5 and manufactured and marketed by Alexion Pharmaceuticals under the tradename Soliris. Eculizumab has been approved by the U.S. FDA for the treatment of PNH and aHUS. 
     In one embodiment, an active compound or its salt or composition as described herein may be provided together with a compound that inhibits complement factor D. In one embodiment of the invention, an active compound or its salt or composition as described herein as described herein can be used in combination or alternation with a compound described in Biocryst Pharmaceuticals U.S. Pat. No. 6,653,340 titled “Compounds useful in the complement, coagulate and kallikrein pathways and method for their preparation” describes fused bicyclic ring compounds that are potent inhibitors of Factor D; Novartis PCT patent publication WO2012/093101 titled “Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration” describes certain Factor D inhibitors; Novartis PCT patent publications WO2014/002051, WO2014/002052, WO2014/002053, WO2014/002054, WO2014/002057, WO2014/002058, WO2014/002059, WO2014/005150, WO2014/009833, WO 2013/164802, WO 2015/009616, WO 2015/066241, Bristol-Myers Squibb PCT patent publication WO2004/045518 titled “Open chain prolyl urea-related modulators of androgen receptor function”; Japan Tobacco Inc. PCT patent publication WO1999/048492 titled “Amide derivatives and nociceptin antagonists”; Ferring B. V. and Yamanouchi Pharmaceutical Co. LTD. PCT patent publication WO1993/020099 titled “CCK and/or gastrin receptor ligands”; Alexion Pharmaceuticals PCT patent publication WO1995/029697 titled “Methods and compositions for the treatment of glomerulonephritis and other inflammatory diseases”; or Achillion Pharmaceuticals filed PCT Patent Application No. PCT/US2015/017523 and U.S. patent application Ser. No. 14/631,090 titled “Alkyne Compounds for Treatment of Complement Mediated Disorders”; PCT Patent Application No. PCT/US2015/017538 and U.S. patent application Ser. No. 14/631,233 titled “Amide Compounds for Treatment of Complement Mediated Disorders”; PCT Patent Application No. PCT/US2015/017554 and U.S. patent application Ser. No. 14/631,312 titled “Amino Compounds for Treatment of Complement Mediated Disorders”; PCT Patent Application No. PCT/US2015/017583 and U.S. patent application Ser. No. 14/631,440 titled “Carbamate, Ester, and Ketone Compounds for Treatment of Complement Mediated Disorders”; PCT Patent Application No. PCT/US2015/017593 and U.S. patent application Ser. No. 14/631,625 titled “Aryl, Heteroaryl, and Heterocyclic Compounds for Treatment of Complement Mediated Disorders”; PCT Patent Application No. PCT/US2015/017597 and U.S. patent application Ser. No. 14/631,683 titled “Ether Compounds for Treatment of Complement Mediated Disorders”; PCT Patent Application No. PCT/US2015/017600 and U.S. patent application Ser. No. 14/631,785 titled “Phosphonate Compounds for Treatment of Complement Mediated Disorders”; and PCT Patent Application No. PCT/US2015/017609 and U.S. patent application Ser. No. 14/631,828 titled “Compounds for Treatment of Complement Mediated Disorders.” 
     In one embodiment, an active compound or its salt or composition as described herein is administered in combination with an anti-inflammatory drug, antimicrobial agent, anti-angiogenesis agent, immunosuppressant, antibody, steroid, ocular antihypertensive drug or combinations thereof. Examples of such agents include amikacin, anecortane acetate, anthracenedione, anthracycline, an azole, amphotericin B, bevacizumab, camptothecin, cefuroxime, chloramphenicol, chlorhexidine, chlorhexidine digluconate, clortrimazole, a clotrimazole cephalosporin, corticosteroids, dexamethasone, desamethazone, econazole, eftazidime, epipodophyllotoxin, fluconazole, flucytosine, fluoropyrimidines, fluoroquinolines, gatifloxacin, glycopeptides, imidazoles, itraconazole, ivermectin, ketoconazole, levofloxacin, macrolides, miconazole, miconazole nitrate, moxifloxacin, natamycin, neomycin, nystatin, ofloxacin, polyhexamethylene biguanide, prednisolone, prednisolone acetate, pegaptanib, platinum analogues, polymicin B, propamidine isethionate, pyrimidine nucleoside, ranibizumab, squalamine lactate, sulfonamides, triamcinolone, triamcinolone acetonide, triazoles, vancomycin, anti-vascular endothelial growth factor (VEGF) agents, VEGF antibodies, VEGF antibody fragments, vinca alkaloid, timolol, betaxolol, travoprost, latanoprost, bimatoprost, brimonidine, dorzolamide, acetazolamide, pilocarpine, ciprofloxacin, azithromycin, gentamycin, tobramycin, cefazolin, voriconazole, gancyclovir, cidofovir, foscarnet, diclofenac, nepafenac, ketorolac, ibuprofen, indomethacin, fluoromethalone, rimexolone, anecortave, cyclosporine, methotrexate, tacrolimus and combinations thereof. 
     In one embodiment of the present invention, an active compound or its salt or composition as described herein can be administered in combination or alternation with at least one immunosuppressive agent. The immunosuppressive agent as non-limiting examples, may be a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g. Sirolimus (RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g. ridaforolimus, azathioprine, campath 1H, a S1P receptor modulator, e.g. fingolimod or an analogue thereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA41g (Abatacept), belatacept, LFA31g, etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®), infliximab (Remicade®), an anti-LFA-1 antibody, natalizumab (Antegren®), Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab, Alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, tocilizumab (Actemra), siltuximab (Sylvant), secukibumab (Cosentyx), ustekinumab (Stelara), risankizumab, sifalimumab, aspirin and ibuprofen. 
     Examples of anti-inflammatory agents include methotrexate, dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate, fluromethalone acetate, fluromethalone alcohol, lotoprendol etabonate, medrysone, prednisolone acetate, prednisolone sodium phosphate, difluprednate, rimexolone, hydrocortisone, hydrocortisone acetate, lodoxamide tromethamine, aspirin, ibuprofen, suprofen, piroxicam, meloxicam, flubiprofen, naproxan, ketoprofen, tenoxicam, diclofenac sodium, ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac, flurbiprofen sodium, suprofen, celecoxib, naproxen, rofecoxib, glucocorticoids, diclofenac, and any combination thereof. In one embodiment, an active compound or its salt or composition as described herein is combined with one or more non-steroidal anti-inflammatory drugs (NSAIDs) selected from naproxen sodium (Anaprox), celecoxib (Celebrex), sulindac (Clinoril), oxaprozin (Daypro), salsalate (Disalcid), diflunisal (Dolobid), piroxicam (Feldene), indomethacin (Indocin), etodolac (Lodine), meloxicam (Mobic), naproxen (Naprosyn), nabumetone (Relafen), ketorolac tromethamine (Toradol), naproxen/esomeprazole (Vimovo), and diclofenac (Voltaren), and combinations thereof. 
     In one embodiment, an active compound or its salt or composition as described herein is administered in combination or alteration with an omega-3 fatty acid or a peroxisome proliferator-activated receptor (PPARs) agonist. Omega-3 fatty acids are known to reduce serum triglycerides by inhibiting DGAT and by stimulating peroxisomal and mitochondrial beta oxidation. Two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been found to have high affinity for both PPAR-alpha and PPAR-gamma. Marine oils, e.g., fish oils, are a good source of EPA and DHA, which have been found to regulate lipid metabolism. Omega-3 fatty acids have been found to have beneficial effects on the risk factors for cardiovascular diseases, especially mild hypertension, hypertriglyceridemia and on the coagulation factor VII phospholipid complex activity. Omega-3 fatty acids lower serum triglycerides, increase serum HDL-cholesterol, lower systolic and diastolic blood pressure and the pulse rate, and lower the activity of the blood coagulation factor VII-phospholipid complex. Further, omega-3 fatty acids seem to be well tolerated, without giving rise to any severe side effects. One such form of omega-3 fatty acid is a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil containing DHA and EPA and is sold under the trademark Omacor®. Such a form of omega-3 fatty acid is described, for example, in U.S. Pat. Nos. 5,502,077, 5,656,667 and 5,698,594, the disclosures of which are incorporated herein by reference. 
     Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. There are three distinct PPAR subtypes that are the products of different genes and are commonly designated PPAR-alpha, PPAR-beta/delta (or merely, delta) and PPAR-gamma. General classes of pharmacological agents that stimulate peroxisomal activity are known as PPAR agonists, e.g., PPAR-alpha agonists, PPAR-gamma agonists and PPAR-delta agonists. Some pharmacological agents are combinations of PPAR agonists, such as alpha/gamma agonists, etc., and some other pharmacological agents have dual agonist/antagonist activity. Fibrates such as fenofibrate, bezafibrate, clofibrate and gemfibrozil, are PPAR-alpha agonists and are used in patients to decrease lipoproteins rich in triglycerides, to increase HDL and to decrease atherogenic-dense LDL. Fibrates are typically orally administered to such patients. Fenofibrate or 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester, has been known for many years as a medicinally active principle because of its efficacy in lowering blood triglyceride and cholesterol levels. 
     In one embodiment, the present invention provides a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination with an anti-VEGF agent. Non-limiting examples of anti-VEGF agents include, but are not limited to, aflibercept (Eylea®; Regeneron Pharmaceuticals); ranibizumab (Lucentis®: Genentech and Novartis); and pegaptanib (Macugen®; OSI Pharmaceuticals and Pfizer); Bevacizumab (Avastin; Genentech/Roche); anecortane acetate, squalamine lactate, and corticosteroids, including, but not limited to, triamcinolone acetonide. 
     In one embodiment, the present invention provides a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein with an additional inhibitor of the complement system or another active compound with a different biological mechanism of action. In another embodiment, the present invention provides a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination or alternation with eculizumab. In another embodiment, the present invention provides a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination or alternation with CP40. In one embodiment, the additional agent is PEGylated-CP40. CP40 is a peptide inhibitor that shows a strong binding affinity for C3b and inhibits hemolysis of paroxysmal nocturnal hemoglobinuria (PNH) erythrocytes. 
     In one embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of a composition comprising an active compound or its salt or composition as described herein in combination or alternation with an additional inhibitor of the complement system, or an active agent that functions through a different mechanism of action. In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination or alternation with methotrexate. In certain embodiments, an active compound or its salt or composition as described herein is administered in combination or alternation with at least one additional therapeutic agent selected from: salicylates including aspirin (Anacin, Ascriptin, Bayer Aspirin, Ecotrin) and salsalate (Mono-Gesic, Salgesic); nonsteroidal anti-inflammatory drugs (NSAIDs); nonselective inhibitors of the cyclo-oxygenase (COX-1 and COX-2) enzymes, including diclofenac (Cataflam, Voltaren), ibuprofen (Advil, Motrin), ketoprofen (Orudis), naproxen (Aleve, Naprosyn), piroxicam (Feldene), etodolac (Lodine), indomethacin, oxaprozin (Daypro), nabumetone (Relafen), and meloxicam (Mobic); selective cyclo-oxygenase-2 (COX-2) inhibitors including Celecoxib (Celebrex); disease-modifying antirheumatic drugs (DMARDs), including azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), gold salts (Ridaura, Solganal, Aurolate, Myochrysine), hydroxychloroquine (Plaquenil), leflunomide (Arava), methotrexate (Rheumatrex), penicillamine (Cuprimine), and sulfasalazine (Azulfidine); biologic drugs including abatacept (Orencia), etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), and anakinra (Kineret); corticosteroids including betamethasone (Celestone Soluspan), cortisone (Cortone), dexamethasone (Decadron), methylprednisolone (SoluMedrol, DepoMedrol), prednisolone (Delta-Cortef), prednisone (Deltasone, Orasone), and triamcinolone (Aristocort); gold salts, including Auranofin (Ridaura); Aurothioglucose (Solganal); Aurolate; Myochrysine; or any combination thereof. 
     In one embodiment, the present invention provides a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination or alternation with an additional inhibitor of the complement system, or an active agent that functions through a different mechanism of action. In another embodiment, the present invention provides a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination or alternation with a corticosteroid. Examples of corticosteroids include, but are not limited to, prednisone, dexamethasone, solumedrol, and methylprednisolone. In one embodiment, an active compound or its salt or composition as described herein is combined with at least one anti-multiple sclerosis drug, for example, selected from: Aubagio (teriflunomide), Avonex (interferon beta-1a), Betaseron (interferon beta-1b), Copaxone (glatiramer acetate), Extavia (interferon beta-1b), Gilenya (fingolimod), Lemtrada (alemtuzumab), Novantrone (mitoxantrone), Plegridy (peginterferon beta-1a), Rebif (interferon beta-1a), Tecfidera (dimethyl fumarate), Tysabri (natalizumab), Solu-Medrol (methylprednisolone), High-dose oral Deltasone (prednisone), H.P. Acthar Gel (ACTH), or a combination thereof. 
     In one embodiment, an active compound or its salt or composition as described herein is useful in a combination with another pharmaceutical agent to ameliorate or reduce a side effect of the agent. For example, in one embodiment, an active compound or its salt or composition as described herein may be used in combination with adoptive cell transfer therapies to reduce an associated inflammatory response associated with such therapies, for example, a cytokine mediated response such as cytokine release syndrome. In one embodiment, the adoptive cell transfer therapy includes the use of a chimeric antigen receptor T-Cell (CAR T). In one embodiment, the adoptive cell transfer therapy includes the use of a chimeric antigen receptor T-Cell (CAR T) or a dendritic cell to treat a hematologic or solid tumor, for example, a B-cell related hematologic cancer. In one embodiment, the hematologic or solid tumor is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin&#39;s lymphoma, chronic lymphocytic leukemia (CLL), pancreatic cancer, glioblastoma, or a cancer that expresses CD19. 
     In an additional alternative embodiment, an active compound or its salt or composition as described herein may be provided in combination with eculizumab for the treatment of PNH, aHUSs, STEC-HUS, ANCA-vasculitis, AMD, CAD, chronic hemolysis, neuromyelitis optica, or transplantation rejection. In one embodiment, an active compound or its salt or composition as described herein may be provided in combination with compstatin or a compstatin derivative for the treatment of PNH, aHUSs, STEC-HUS, ANCA-vasculitis, AMD, CAD, chronic hemolysis, neuromyelitis optica, or transplantation rejection. 
     In one embodiment, an active compound or its salt or composition as described herein may be provided in combination with rituxan for the treatment of a complement mediated disorder. In one embodiment, the complement mediated disorder is, for example, rheumatoid arthritis, Granulomatosis with Polyangiitis (GPA) (Wegener&#39;s Granulomatosis), and Microscopic Polyangiitis (MPA). In one embodiment, the disorder is Lupus. 
     In one embodiment, an active compound or its salt or composition as described herein may be provided in combination with cyclophosphamide for the treatment of a complement mediated disorder. In one embodiment, the disorder is an autoimmune disease. In one embodiment, the complement mediated disorder is, for example, rheumatoid arthritis, Granulomatosis with Polyangiitis (GPA) (Wegener&#39;s Granulomatosis), and Microscopic Polyangiitis (MPA). In one embodiment, the disorder is Lupus. 
     In one embodiment, an active compound or its salt or composition as described herein is dosed in combination with a conventional DLE treatment for the treatment of lupus to a subject in need thereof. 
     Examples of conventional DLE treatments include topical corticosteroid ointments or creams, such as triamcinolone acetonide, fluocinolone, flurandrenolide, betamethasone valerate, or betamethasone dipropionate. Resistant plaques can be injected with an intradermal corticosteroid. Other potential DLE treatments include calcineurin inhibitors such as pimecrolimus cream or tacrolimus ointment. Particularly resistant cases can be treated with systemic antimalarial drugs, such as hydroxychloroquine (PLAQUENIL). 
     In one embodiment, an active compound or its salt or composition as described herein may be provided in combination with methotrexate for the treatment of Lupus. 
     In one embodiment, an active compound or its salt or composition as described herein may be provided in combination with azathioprine for the treatment of Lupus. 
     In one embodiment, an active compound or its salt or composition as described herein may be provided in combination with a non-steroidal anti-inflammatory drug for the treatment of Lupus. 
     In one embodiment, an active compound or its salt or composition as described herein may be provided in combination with a corticosteroid for the treatment of Lupus. 
     In one embodiment, an active compound or its salt or composition as described herein may be provided in combination with a belimumab (Benlysta) for the treatment of Lupus. 
     In one embodiment, an active compound or its salt or composition as described herein may be provided in combination with hydroxychloroquine (Plaquenil) for the treatment of Lupus. 
     In one embodiment, an active compound or its salt or composition as described herein may be provided in combination with sifalimumab for the treatment of Lupus. 
     In one embodiment, an active compound or its salt or composition as described herein may be provided in combination with OMS721 (Omeros) for the treatment of a complement mediated disorder. In one embodiment, an active compound or its salt or composition as described herein may be provided in combination with OMS906 (Omeros) for the treatment of a complement mediated disorder. In one embodiment, the complement mediated disorder is, for example, thrombotic thrombocytopenic purpura (TTP) or aHUS. 
     In one embodiment, an active compound or its salt or composition as described herein may be provided in combination with an anti-inflammatory agent, immunosuppressive agent, or anti-cytokine agent for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics (e.g. adoptive T-cell therapy (ACT) such as CAR T-cell therapy, or monoclonal antibody therapy). In one embodiment, an active compound or its salt or composition as described herein may be provided in combination with a corticosteroid, for example prednisone, dexamethasone, solumedrol, and methylprednisolone, and/or anti-cytokine compounds targeting, e.g., IL-4, IL-10, IL-11, IL-13 and TGFβ. In one embodiment, an active compound or its salt or composition as described herein may be provided in combination with an anti-cytokine inhibitor including, but are not limited to, adalimumab, infliximab, etanercept, protopic, efalizumab, alefacept, anakinra, siltuximab, secukibumab, ustekinumab, golimumab, and tocilizumab, or a combination thereof. Additional anti-inflammatory agents that can be used in combination with an active compound or its salt or composition as described herein include, but are not limited to, non-steroidal anti-inflammatory drug(s) (NSAIDs); cytokine suppressive anti-inflammatory drug(s) (CSAIDs); CDP-571/BAY-10-3356 (humanized anti-TNFα antibody; Celltech/Bayer); cA2/infliximab (chimeric anti-TNFα antibody; Centocor); 75 kdTNFR-IgG/etanercept (75 kD TNF receptor-IgG fusion protein; Immunex); 55 kdTNF-IgG (55 kD TNF receptor-IgG fusion protein; Hoffmann-LaRoche); IDEC-CE9.1/SB 210396 (non-depleting primatized anti-CD4 antibody; IDEC/SmithKline); DAB 486-IL-2 and/or DAB 389-IL-2 (IL-2 fusion proteins; Seragen); Anti-Tac (humanized anti-IL-2Rα; Protein Design Labs/Roche); IL-4 (anti-inflammatory cytokine; DNAX/Schering); IL-10 (SCH 52000; recombinant IL-10, anti-inflammatory cytokine; DNAX/Schering); IL-4; IL-10 and/or IL-4 agonists (e.g., agonist antibodies); IL-1RA (IL-1 receptor antagonist; Synergen/Amgen); anakinra (Kineret®/Amgen); TNF-bp/s-TNF (soluble TNF binding protein); R973401 (phosphodiesterase Type IV inhibitor); MK-966 (COX-2 Inhibitor); Iloprost, leflunomide (anti-inflammatory and cytokine inhibiton); tranexamic acid (inhibitor of plasminogen activation); T-614 (cytokine inhibitor); prostaglandin E1; Tenidap (non-steroidal anti-inflammatory drug); Naproxen (non-steroidal anti-inflammatory drug); Meloxicam (non-steroidal anti-inflammatory drug); Ibuprofen (non-steroidal anti-inflammatory drug); Piroxicam (non-steroidal anti-inflammatory drug); Diclofenac (non-steroidal anti-inflammatory drug); Indomethacin (non-steroidal anti-inflammatory drug); Sulfasalazine; Azathioprine; ICE inhibitor (inhibitor of the enzyme interleukin-1β converting enzyme); zap-70 and/or lck inhibitor (inhibitor of the tyrosine kinase zap-70 or lck); TNF-convertase inhibitors; anti-IL-12 antibodies; anti-IL-18 antibodies; interleukin-11; interleukin-13; interleukin-17 inhibitors; gold; penicillamine; chloroquine; chlorambucil; hydroxychloroquine; cyclosporine; cyclophosphamide; anti-thymocyte globulin; anti-CD4 antibodies; CD5-toxins; orally-administered peptides and collagen; lobenzarit disodium; Cytokine Regulating Agents (CRAB) HP228 and HP466 (Houghten Pharmaceuticals, Inc.); ICAM-1 antisense phosphorothioate oligo-deoxynucleotides (ISIS 2302; Isis Pharmaceuticals, Inc.); soluble complement receptor 1 (TP10; T Cell Sciences, Inc.); prednisone; orgotein; glycosaminoglycan polysulphate; minocycline; anti-IL2R antibodies; marine and botanical lipids (fish and plant seed fatty acids); auranofin; phenylbutazone; meclofenamic acid; flufenamic acid; intravenous immune globulin; zileuton; azaribine; mycophenolic acid (RS-61443); tacrolimus (FK-506); sirolimus (rapamycin); amiprilose (therafectin); cladribine (2-chlorodeoxyadenosine). 
     In a specific embodiment, an active compound or its salt or composition as described herein may be provided in combination with a corticosteroid for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics. In another embodiment, an active compound or its salt or composition as described herein may be provided in combination with etarnercept for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics. In another embodiment, an active compound or its salt or composition as described herein may be provided in combination with tocilizumab for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics. In another embodiment, an active compound or its salt or composition as described herein may be provided in combination with etarnercept and tocilizumab for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics. In another embodiment, an active compound or its salt or composition as described herein may be provided in combination with infliximab for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics. In another embodiment, an active compound or its salt or composition as described herein may be provided in combination with golimumab for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics. 
     VI. Combinations for Prophylactic or Concommitant Anti-Bacterial Therapy 
     In one aspect of the present invention, a method is provided for treating a host in need thereof that comprises administering an effective amount of a prophylactic anti-bacterial vaccine prior to administration of an active compound or its salt or composition for any of the disorders described herein. In another aspect of the present invention, a method is provided for treating a host in need thereof that comprises administering an effective amount of a prophylactic anti-bacterial drug, such as a pharmaceutical drug, prior to administration of an active compound or its salt or composition for any of the disorders described herein. In one aspect of the present invention, a method is provided for treating a host in need thereof that comprises administering an effective amount of an anti-bacterial vaccine after administration of an active compound or its salt or composition for any of the disorders described herein. In another aspect of the present invention, a method is provided for treating a host in need thereof that comprises administering an effective amount of an anti-bacterial drug, such as a pharmaceutical drug, after administration of an active compound or its salt or composition for any of the disorders described herein. In one embodiment, the disorder is PNH or aHUS. In one embodiment, the host has received an organ or other tissue or biological fluid transplant. In one embodiment, the host is also administered eculizumab. 
     In one aspect of the present invention, an active compound or its salt or composition as described herein is administered to a host concomitantly to a subject following the prophylactic administration of a vaccine against a bacterial infection. In one embodiment, the complement mediated disorder is PNH or aHUS. In one embodiment, the subject has received an organ or other tissue or biological fluid transplant. In one embodiment, the subject is also administered eculizumab. 
     In one aspect of the present invention, an active compound or its salt or composition as described herein is administered to a subject concomitantly with the prophylactic administration of a vaccine against a bacterial infection. In one embodiment, the complement mediated disorder is PNH or aHUS. In one embodiment, the subject has received an organ or other tissue or biological fluid transplant. In one embodiment, the subject is also administered eculizumab. 
     In one aspect of the present invention, an active compound or its salt or composition as described herein is administered to a subject and, during the administration period of the compound or salt, a vaccine against a bacterial infection is administered to the subject. In one embodiment, the complement mediated disorder is PNH or aHUS. In one embodiment, the subject has received an organ or other tissue or biological fluid transplant. In one embodiment, the subject is also administered eculizumab. 
     In one aspect of the present invention, the subject is administered an active compound or its salt or composition as described herein in combination with an antibiotic compound for the duration of factor D inhibitor administration. In one embodiment, the complement mediated disorder is PNH or aHUS. In one embodiment, the subject has received an organ or other tissue or biological fluid transplant. In one embodiment, the subject is also administered eculizumab. 
     In one aspect of the present invention, an active compound or its salt or composition as described herein is administered to a subject following the prophylactic administration of a vaccine against a bacterial infection, and in combination with an antibiotic compound for the duration of factor D inhibitor administration. In one embodiment, the complement mediated disorder is PNH or aHUS. In one embodiment, the subject has received an organ or other tissue or biological fluid transplant. In one embodiment, the subject is also administered eculizumab. 
     In one embodiment, the subject, prior to receiving an active compound or its salt or composition as described herein, is vaccinated against a bacterial infection caused by the bacterium  Neisseria meningitidis . In one embodiment, the subject is vaccinated against a bacterial infection caused by the bacterium  Haemophilus influenzae . In one embodiment, the  Haemophilus influenzae  is  Haemophilus influenzae  serotype B (Hib). In one embodiment, the subject is vaccinated against a bacterial infection caused by  Streptococcus pneumoniae . In one embodiment, the subject is vaccinated against a bacterial infection caused by the bacterium  Nisseria meningitidis, Haemophilus influenzae , or  Streptococcus pneumoniae , or a combination of one or more of  Nisseria meningitidis, Haemophilus influenzae , or  Streptococcus pneumoniae . In one embodiment, the subject is vaccinated against a bacterial infection caused by the bacterium  Nisseria meningitidis, Haemophilus influenzae , and  Streptococcus pneumoniae.    
     In other embodiments, the subject is vaccinated against a bacterial infection caused by a bacterium selected from a Gram-negative bacterium. In one embodiment, the subject is vaccinated against a bacterial infection caused by a bacterium selected from a Gram-positive bacterium. In one embodiment, the subject is vaccinated against a bacterial infection caused by the bacterium  Nisseria meningitidis, Haemophilus influenzae , or  Streptococcus pneumoniae , or a combination of one or more of  Nisseria meningitidis, Haemophilus influenzae , or  Streptococcus pneumoniae , and one or more of, but not limited to,  Bacillus anthracis, Bordetella pertussis, Clostridium tetani, Corynebacterium diphtheria, Coxiella burnetii, Mycobacterium tuberculosis, Salmonella typhi, Vibrio cholerae, Anaplasma phagocytophilum, Ehrlichia ewingii, Ehrlichia chaffeensis, Ehrlichia canis, Neorickettsia sennetsu, Mycobacterium leprae, Borrelia burgdorferi, Borrelia mayonii, Borrelia afzelii, Borrelia garinii, Mycobacterium bovis, Staphylococcus aureus, Streptococcus pyogenes, Treponema pallidum, Francisella tularensis, Yersinia pestis,    
     In one embodiment, the subject is vaccinated with one or more vaccines selected from, but not limited to, typhoid vaccine, live (Vivotif Berna Vaccine, PaxVax), typhoid Vi polysaccharide vaccine (Typhim Vi, Sanofi), pneumococcal 23-polyvalent vaccine, PCV13 (Pneumovax 23, Merck), pneumococcal 7-valent vaccine, PCV7 (Prevnar, Pfizer), pneumococcal 13-valent vaccine, PCV13 (Prevnar 13, Pfizer),  Haemophilus  b conjugate (prp-t) vaccine (ActHIB, Sanofi; Hibrix, GSK),  Haemophilus  b conjugate (hboc) vaccine (HibTITER, Neuron Biotech),  Haemophilus  b conjugate (prp-omp) vaccine (PedvaxHlB, Merck),  Haemophilus  b conjugate (prp-t) vaccine/meningococcal conjugate vaccine (MenHibrix, GSK),  Haemophilus  b conjugate (prp-t) vaccine/meningococcal conjugate vaccine/Hepatitis B vaccine (Comvax, Merck), meningococcal polysaccharide vaccine (Menomune A/C/Y/W-135, Sanofi), meningococcal conjugate vaccine/diphtheria CRM197 conjugate (Menveo, GSK; Menactra, Sanofi), meningococcal group B vaccine (Bexsero, GSK; Trumenba, Pfizer), anthrax vaccine adsorbed (Biothrax, Emergent Biosolutions), tetanus toxoid (Te Anatoxal Berna, Hendricks Regional Health),  Bacillus  Calmette and Guérin, live, intravesical (TheraCys, Sanofi; Tice BCG, Organon), cholera vaccine, live, oral (Vachora, Sanofi; Dukoral, SBL Vaccines; ShanChol, Shantha Biotec; Micromedex, Truven Health), tetanus toxoids and diphtheria absorbed (Tdap; Decavac, Sanofi; Tenivac, Sanofi; td, Massachusetts Biological Labs), diphtheria and tetanus toxois and pertussis (DTap; Daptacel, Sanofi; Infanrix, GSK; Tripedia, Sanofi), diphtheria and tetanus toxois and pertussis/polio (Kinrix, GSK; Quadracel, Sanofi), diphtheria and tetanus toxois and pertussis tetanus/hepatitis B/polio (Pediarix, GSK), diphtheria and tetanus toxois and pertussis/polio,  Haemophilus  influenza tybe b (Pentacel, Sanofi), and/or diphtheria, and pertussis (Tdap; Boostrix, GSK; Adacel, Sanofi), or a combination thereof. 
     As described above, a subject receiving a compound of the present invention to treat a disorder is prophylactically administered an antibiotic compound in addition to a factor D inhibitor described herein. In one embodiment, the subject is administered an antibiotic compound for the duration of administration of the active compound to reduce the development of a bacterial infection. Antibiotic compounds for concomitant administration with a factor D inhibitor described herein can be any antibiotic useful in preventing or reducing the effect of a bacterial infection. Antibiotics are well known in the art and include, but are not limited to, amikacin (Amikin), gentamicin (Garamycin), kanamycin (Kantrex), neomycin (Neo-Fradin), netilmicin (Netromycin), tobramycin (Nebcin), paromomycin (Humatin), streptomycin, spectinomycin (Trobicin), geldanamycin, herbimycin, rifaximin (Xifaxan), loracarbef (Lorabid), ertapenem (Invanz), doripenem (Doribax), imipenem/cilastatin (Primaxin), meropenem (Merrem), cefadroxil (Duricef), cefazolin (Ancef), cefalotin/cefalothin (Keflin), cephalexin (Keflex), cefaclor (Distaclor), cefamandole (Mandol), cefoxitin (Mefoxin), cefprozil (Cefzil), cefuroxime (Ceftin, Zinnat), cefixime (Cefspan), cefdinir (Omnicef, Cefdiel), cefditoren (Spectracef, Meiact), cefoperazone (Cefobid), cefotaxime (Claforan), cefpodoxime (Vantin) ceftazidime (Fortaz), ceftibuten (Cedax), ceftizoxime (Cefizox), ceftriaxone (Rocephin), cefepime (Maxipime), ceftaroline fosamil (Teflaro), ceftobiprole (Zeftera), teicoplanin (Targocid), vancomycin (Vancocin), telavancin (Vibativ), dalbavancin (Dalvance), oritavancin (Orbactiv), clindamycin (Cleocin), lincomycin (Lincocin), daptomycin (Cubicin), azithromycin (Zithromax, Sumamed, Xithrone), clarithromycin (Biaxin), dirithromycin (Dynabac), erythromycin (Erythocin, Erythroped), roxithromycin, troleandomycin (Tao), telithromycin (Ketek), spiramycin (Rovamycine), aztreonam (Azactam), furazolidone (Furoxone), nitrofurantoin (Macrodantin, Macrobid), linezolid (Zyvox), posizolid, radezolid, torezolid, amoxicillin (Novamox, Amoxil), ampicillin (Principen), azlocillin, carbenicillin (Geocillin), cloxacillin (Tegopen), dicloxacillin (Dynapen), flucloxacillin (Floxapen), mezlocillin (Mezlin), methicillin (Staphcillin), nafcillin (Unipen), oxacillin (Prostaphlin), penicillin G (Pentids), penicillin V (Veetids (Pen-Vee-K), piperacillin (Pipracil), penicillin G (Pfizerpen), temocillin (Negaban), ticarcillin (Ticar), amoxicillin/clavulanate (Augmentin), ampicillin/sulbactam (Unasyn), piperacillin/tazobactam (Zosyn), ticarcillin/clavulanate (Timentin), bacitracin, colistin (Coly-Mycin-S), polymyxin B, ciprofloxacin (Cipro, Ciproxin, Ciprobay), enoxacin (Penetrex), gatifloxacin (Tequin), gemifloxacin (Factive), levofloxacin (Levaquin), lomefloxacin (Maxaquin), moxifloxacin (Avelox), nalidixic acid (NegGram), norfloxacin (Noroxin), ofloxacin (Floxin, Ocuflox), trovafloxacin (Trovan), grepafloxacin (Raxar), sparfloxacin (Zagam), temafloxacin (Omniflox), mafenide (Sulfamylon), sulfacetamide (Sulamyd, Bleph-10), sulfadiazine (Micro-Sulfon), silver sulfadiazine (Silvadene), sulfadimethoxine (Di-Methox, Albon), sulfamethizole (Thiosulfil Forte), sulfamethoxazole (Gantanol), sulfanilamide, sulfasalazine (Azulfidine), sulfisoxazole (Gantrisin), trimethoprim-sulfamethoxazole (Co-trimoxazole) (TMP-SMX) (Bactrim, Septra), sulfonamidochrysoidine (Prontosil), demeclocycline (Declomycin), doxycycline (Vibramycin), minocycline (Minocin), oxytetracycline (Terramycin), tetracycline (Sumycin, Achromycin V, Steclin), clofazimine (Lamprene), dapsone (Avlosulfon), capreomycin (Capastat), cycloserine (Seromycin), ethambutol (Myambutol), ethionamide (Trecator), isoniazid (I.N.H.), pyrazinamide (Aldinamide), rifampicin (Rifadin, Rimactane), rifabutin (Mycobutin), rifapentine (Priftin), streptomycin, arsphenamine (Salvarsan), chloramphenicol (Chloromycetin), fosfomycin (Monurol, Monuril), fusidic acid (Fucidin), metronidazole (Flagyl), mupirocin (Bactroban), platensimycin, quinupristin/dalfopristin (Synercid), thiamphenicol, tigecycline (Tigacyl), tinidazole (Tindamax Fasigyn), trimethoprim (Proloprim, Trimpex), and/or teixobactin, or a combination thereof. 
     In one embodiment, the subject is administered a prophylactic antibiotic selected from cephalosporin, for example, ceftriaxone or cefotaxime, ampicillin-sulbactam, Penicillin G, ampicillin, chloramphenicol, fluoroquinolone, aztreonam, levofloxacin, moxifloxacin, gemifloxacin, vancomycin, clindamycin, cefazolin, azithromycin, meropenem, ceftaroline, tigecycline, clarithromycin, moxifloxacin, trimethoprim/sulfamethoxazole, cefuroxime, axetil, ciprofloxacin, rifampin, minocycline, spiramycin, and cefixime, or a combination of two or more thereof. 
     VII. Process of Preparation of Compounds of Formula I, Formula I′ and Formula I″ 
     Abbreviations 
     
         
         ACN Acetonitrile 
         Ac Acetyl 
         Ac 2 O Acetic anhydride 
         AcOEt, EtOAc ethyl acetate 
         AcOH Acetic acid 
         Boc 2 O di-tert-butyl dicarbonate 
         Bu Butyl 
         CAN Ceric ammonium nitrate 
         CBz Carboxybenzyl 
         CDI Carbonyldiimidazole 
         CH 3 OH, MeOH Methanol 
         CsF Cesium fluoride 
         CuI Cuprous iodide 
         DCM, CH 2 Cl 2  Dichloromethane 
         DIEA, DIPEA N,N-diisopropylethylamine 
         DMA N,N-dimethyl acetamide 
         DMAP 4-Dimethylaminopyridine 
         DMF N,N-dimethylformamide 
         DMS Dimethyl sulfide 
         DMSO Dimethylsulfoxide 
         DPPA Diphenyl phosphoryl azide 
         EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide 
         Et Ethyl 
         Et 3 N, TEA Triethylamine 
         EtOAc Ethylacetate 
         EtOH Ethanol 
         HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate 
         HCl Hydrochloric acid 
         HOBT Hydroxybenzotriazole 
         iBu, i-Bu, isoBu Isobutyl 
         iPr, i-Pr, isoPr Isopropyl 
           i Pr 2 NEt N,N-diisopropylethylamine 
         K 2 CO 3  Potassium carbonate 
         K 2 CO 3  Potassium carbonate 
         LiOH Lithium hydroxide 
         Me Methyl 
         Mel Methyl iodide 
         Ms Mesyl 
         MSCl Mesylchloride 
         MTBE Methyl  t butylether 
         Na 2 SO 4  Sodium sulfate 
         NaCl Sodium chloride 
         NaH Sodium hydride 
         NaHCO 3 Sodium bicarbonate 
         NBS N-bromo succinimide 
         NCS N-chloro succinimide 
         NEt 3  Trimethylamine 
         NMP N-Methyl-2-pyrrolidone 
         PCC Pyridinium chlorochromate 
         Pd(OAc) 2  Palladium acetate 
         Pd(dppf)Cl 2 [1,1 ′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II) 
         Pd(PPh 3 ) 2 Cl 2  Bis(triphenylphosphine)palladium(II) dichloride 
         Pd(PPh 3 ) 4  Tetrakis(triphenylphosphine)palladium(0) 
         Pd/C Palladium on carbon 
         Pd 2 (dba) 3  Tris(dibenzylideneacetone)dipalladium(0) 
         PMB 4-Methoxybenzyl ether 
         PPh 3  Triphenylphosphine 
         Pr Propyl 
         Py, py Pyridine 
         RT Room temperature 
         TBAF Tetra-n-butylammonium fluoride 
         TBAT Tetrabutylammonium difluorotriphenylsilicate 
         tBu, t-Bu Tertbutyl 
         tBuOK Potassium tert-butoxide 
         TEA Trimethylamine 
         Tf 2 O Trifluoromethanesulfonic anhydride 
         TFA Trifluoroacetic acid 
         THF Tetrahydrofuran 
         TMS Trimethylsilane 
         TMSBr Bromotrimethylsilane 
         TMSCl Chlorotrimethylsilane 
         tR Retention time 
         Troc 2,2,2-Trichlorethoxycarbonyl chloride 
         Zn(CN) 2  Zinc cyanide
 
General Methods
 
       
    
     All nonaqueous reactions were performed under an atmosphere of dry argon or nitrogen gas using anhydrous solvents. The progress of reactions and the purity of target compounds were determined using one of the two liquid chromatography (LC) methods listed below. The structure of starting materials, intermediates, and final products was confirmed by standard analytical techniques, including NMR spectroscopy and mass spectrometry. 
     LC Method A
         Instrument: Waters Acquity Ultra Performance LC   Column: ACQUITY UPLC BEH C18 2.1×50 mm, 1.7 μm   Column Temperature: 40° C.   Mobile Phase: Solvent A: H 2 O+0.05% FA; Solvent B: CH 3 CN+0.05% FA   Flow Rate: 0.8 mL/min   Gradient: 0.24 min @ 15% B, 3.26 min gradient (15-85% B), then 0.5 min @ 85% B.   Detection: UV (PDA), ELS, and MS (SQ in EI mode)       

     LC Method B
         Instrument: Shimadzu LC-2010A HT   Column: Athena, C18-WP, 50×4.6 mm, 5   Column Temperature: 40° C.   Mobile Phase: Solvent A: H 2 O/CH 3 OH/FA=90/10/0.1; Solvent B: H 2 O/CH 3 OH/FA=10/90/0.1   Flow Rate: 3 mL/min   Gradient: 0.4 min @ 30% B, 3.4 min gradient (30-100% B), then 0.8 min @ 100% B   Detection: UV (220/254 nm)       

     LC Method C
         Instrument: Agilent 1100/1200 series LC system with DAD detector   Column: Atlantis dC18 (250×4.6) mm, 5 μm   Column Temperature: Ambient   Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile   Flow Rate: 1.0 mL/min   Gradient:       

     
       
         
           
               
               
               
               
               
               
               
             
               
                   
                   
               
               
                   
                 Time (min) 
                 0.0 
                 15 
                 20 
                 23 
                 30 
               
               
                   
                   
               
             
            
               
                   
                 % B 
                 10 
                 100 
                 100 
                 10 
                 10 
               
               
                   
                   
               
            
           
         
       
         
         
           
             Detection: (210-400 nm) 
           
         
       
    
     LC Method D
         Instrument: Shimadzu LC 20AD system with PDA detector   Column: Phenomenex Gemini NX C18 (150×4.6) mm, 5 μm   Column Temperature: Ambient   Mobile Phase A: 10 mM NH 4 OAC in water, Mobile Phase B: Acetonitrile   Flow Rate: 1.0 mL/min   Gradient:       

     
       
         
           
               
               
               
               
               
               
               
             
               
                   
                   
               
               
                   
                 Time (min) 
                 0.0 
                 15 
                 20 
                 23 
                 30 
               
               
                   
                   
               
             
            
               
                   
                 % B 
                 10 
                 100 
                 100 
                 10 
                 10 
               
               
                   
                   
               
            
           
         
       
         
         
           
             Detection: (210-400 nm) 
           
         
       
    
     Example 1. General Route of Synthesis 
     A compound of the present invention can be prepared, for example, from a central core. In one embodiment, for example, the central core Structure 1 is an N-protected amino acid where X 1  is nitrogen and PG=protecting group. In one embodiment, the central core is coupled to an amine to generate an amide of Structure 2 (wherein L-B includes a C(O)N moiety). Structure 2 can then be deprotected to generate Structure 3. Structure 3 is coupled to Structure 4 (A-COOH) to generate a second amide bond, forming a compound within Formula I. The chemistry is illustrated in Route 1. 
     
       
         
         
             
             
         
       
     
     In an alternative embodiment, central core Structure 5 is reacted with a heterocyclic or heteroaryl compound to generate a compound of Structure 6. In one embodiment, Structure 6 is deprotected to generate a carboxylic acid, Structure 7. In one embodiment, Structure 7 is coupled to an amine to generate a compound of Formula I. This chemistry is illustrated in Route 2. 
     
       
         
         
             
             
         
       
     
     In an alternative embodiment, Structure 8 is deprotected to generate an amine which is Structure 9. Structure 9 is then coupled to generate an amide which is Structure 6. Structure 6 is then deprotected to generate a carboxylic acid which is Structure 7. Structure 7 is then coupled to form the amide which falls within Formula I. The chemistry is illustrated in Route 3. 
     
       
         
         
             
             
         
       
     
     In an alternate embodiment, a heteroaryl or aryl moiety, 4-1, is coupled to a central core to generate 4-2. The protected acid, 4-2 is deblocked to form the carboxylic acid, 4-3. The carboxylic acid is then coupled to form an amide (L-B) which is 4-4. The heteroaryl or aryl moiety, A′, can then be further derivatized to add substituents at the X 11 , X 12 , X 13  and X 14  positions to generate compounds of Formula I. This chemistry is illustrated in Route 4. 
     
       
         
         
             
             
         
       
     
     In an alternate embodiment, Structure 5-1 is coupled to an acid, Structure 5-2, to generate Structure 5-3. The carboxylic acid, Structure 5-3, is deblocked to generate a carboxylic acid which is Structure 5-4. Carboxylic acid Structure 5-4 is coupled to an amine to form the product amide (L-B) which is a compound within Formula I. This chemistry is illustrated in Route 5. 
     
       
         
         
             
             
         
       
     
     Example 2. Examples of Central Synthons 
                                           
Z A  is halogen.
 
     In one embodiment, deuterated L-proline synthons are disclosed. Deuterated synthons include, but are not limited to, for example, the following compounds: 
     
       
         
         
             
             
         
       
     
     Structure A can be treated with deuterium oxide to generate Structure B. See, Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655; Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491 and WO 2014/037480 (p. 103). Structure B can be reduced to generate Structure C. See, Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655; Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491. Structure C can be treated with Mitsunobu reaction conditions to generate Structure D. Structure B can be treated with DAST to generate Structure E. See, WO 2014/037480. Structure A can be treated with sodium borodeuteride to generate Structure F. See, Dormoy, J.-R.; Castro, B.  Synthesis  1986, 81-82. Compound F can be used to generate Structure K. See, Dormoy, J.-R.; Castro, B.  Synthesis  1986, 81-82. Structure B can be treated with a deuterated reducing agent, for example sodium borodeuteride to generate Structure G. Structure G can be treated with DAST to generate Structure H. Structure F can be used to generate Structure K. See, Dormoy, J.-R.; Castro, B.  Synthesis  1986, 81-82. Structure G can be used to generate Structure I. Structure J can be prepared according to Hruby, V. J. et al.  J. Am. Chem. Soc.  1979, 101, 202-212. Structures A-J can be used to prepare compounds of Formula I. 
     Example 3. Preparation of Central-L-B Synthons 
     
       
         
         
             
             
         
       
     
     In Route 1a, 5-azaspiro[2.4]heptane-4,5-dicarboxylic acid, 5-(1,1-dimethylethyl) ester, (4,9-, CAS 209269-08-9, can be prepared as described in Tandon, M. et al. Bioorg. Med. Chem. Lett. 1998, 8, 1139-1144. In Step 2, the protected azaspiro[2.4]heptane is coupled to an amine in the presence of an organic solvent, a base and a coupling reagent to generate an amide bond; the L-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the coupling reagent is HATU. In Step 3, the protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N hydrochloric acid. In one embodiment, the organic solvent is dioxane. 
     In Route 1b, (4S) 4-oxazolidinecarboxylic acid, hydrochloride is treated with an amine protecting reagent. In one embodiment, the amine protecting reagent is di-tert-butyl dicarbonate. In another embodiment, 3,4-oxazolidinedicarboxylic acid, 3-(1,1-dim ethyl ethyl) ester, (4S)—, is commercially available from JPM2 Pharmaceuticals. In one embodiment the reaction is carried out in an organic solvent in the presence of a base. In one embodiment, the organic solvent is acetonitrile. In one embodiment, the base is 4-dimentylaminopyridine (DMAP). In Step 2, the protected 4-oxazolidinecarboxylic acid is coupled to an amine in the presence of an organic solvent, a base and a coupling reagent to generate an amide bond; the L-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the coupling reagent is HATU. In Step 3, the protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N hydrochloric acid. In one embodiment, the organic solvent is dioxane. 
     In Route 1c, (S)-5-(tert-Butoxycarbonyl)-5-azaspiro[2.4]heptane-6-caboxylic acid, CAS 1129634-44-1, is commercially available from Ark Pharm. In Step 2, the carboxylic acid is coupled to an amine in the presence of an organic solvent, a base and a coupling reagent to generate an amide bond; the L-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the coupling reagent is HATU. In Step 3, the protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N hydrochloric acid. In one embodiment, the organic solvent is dioxane. 
     
       
         
         
             
             
         
       
     
     In Route 2a, commercially available Boc-L-proline is coupled to an amine in the presence of an organic solvent, a base and a coupling reagent to generate an amide bond; the L-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the coupling reagent is HATU. In Step 2, the Boc protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N hydrochloric acid. In one embodiment, the organic solvent is dioxane. 
     In Route 2b, commercially available (1R,3S,5R)-2-[(tert-butoxy)carbonyl]-2-azabicyclo[3.1.0]hexane-3-carboxylic acid, from Enamine, is coupled to an amine in the presence of an organic solvent, a base and a coupling reagent to generate an amide bond; the L-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the coupling reagent is HATU. In Step 2, the Boc protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N hydrochloric acid. In one embodiment, the organic solvent is dioxane. 
     In Route 2c, commercially available (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid, from Manchester Organics, is coupled to an amine in the presence of an organic solvent, a base and a coupling reagent to generate an amide bond; the L-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the coupling reagent is HATU. In Step 2, the Boc protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N hydrochloric acid. In one embodiment, the organic solvent is dioxane. 
     In Route 2d, commercially available (S)-1-(tert-butoxycarbonyl)indoline-2-carboxylic acid, from Chem-Impex, is coupled to an amine in the presence of an organic solvent, a base and a coupling reagent to generate an amide bond; the L-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the coupling reagent is HATU. In Step 2, the Boc protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N hydrochloric acid. In one embodiment, the organic solvent is dioxane. This chemistry is illustrated in Scheme 2. 
     Additional starting materials that can readily be converted to Central-L-B-Synthons include, but are not limited to: (S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid, CAS 90104-21-5, available from Ark Pharm; cyclopent-1-ene-1,2-dicarboxylic acid, CAS 3128-15-2, purchased from Ark Pharm; imidazole, 1H-imidazole-1,2-dicarboxylic acid, 1-(1,1-dimethylethyl) 2-ethyl ester, CAS 553650-00-3, commercially available from FCH Group; Boc-L-octahydroindole-2-carboxylic acid can be purchased from Chem Impex. The compound, 
                         
can be prepared according to the procedures disclosed in WO 2004/111041; (S)-Boc-5-oxopyrrolidine-2-carboxylic acid is available from the Aldrich Chemical Co.; (1S,2S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]hexane-2-carboxylic acid is available from Ark Pharm; (S)-3-Boc-thiazolidine-2-carboxylic acid is available from Alfa Aesar; (2S,4R)-1-(tert-butoxycarbonyl)-4-chloropyrrolidine-2-carboxylic acid is available from Arch Bioscience; (1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid is available from Ark Pharm; 1,2-pyrrolidinedicarboxylic acid, 3-[[(phenylmethoxy)carbonyl]amino]-, 1-(1,1-dimethylethyl) ester, (2S,3R) can be prepared as disclosed in WO 2004/007501. The Cbz group can be removed and the amino group can be alkylated to generate central core compounds of the present invention.
 
     The compound 
                         
can be prepared as disclosed by Braun, J. V.; Heymons, Albrecht Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1930) 63B, 502-7.
 
     The compounds (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester can be prepared as a mixture according to WO 2012/093101 to Novartis and the regioisomers can be ultimately separated once coupled to generate the central core-L-B synthons. The compound (S)-Boc-5-oxopyrrolidine-2-carboxylic acid is available from the Aldrich Chemical Co. 
     Example 4. Synthesis of L-B Moieties 
     
       
         
         
             
             
         
       
     
     Scheme 4-1: In Step 1 the appropriately substituted dibromo species is coupled with an appropriate boronic acid as known in the art to form a mixture of biaryl and triaryl products from which the desired biaryl compound is isolated. In Step 2 the appropriately substituted biaryl species is converted to the Grignard reagent with activated magnesium. In Step 3 the appropriately substituted aldehyde is treated with the previously prepared Grignard reagent to form an alcohol. In Step 4 the appropriately substituted alcohol is converted to a bromide as known in the art with carbon tetrabromide and triphenyl phosphine. In Step 5 the appropriately substituted bromide is converted to the Grignard reagent with activated magnesium. 
     Example 5. Synthesis of C-L-B Moieties 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Scheme 5-1: In Step 1 the appropriately substituted carboxylic acid is coupled to the appropriately substituted amine as known in the art to form an amide. In Step 2 the appropriately substituted Boc-protected species is deprotected with acid to liberate the free amine. In Step 3 the appropriately substituted amine is Cbz-protected as known in the art to form a protected carboxylic acid. In Step 4 the appropriately substituted carboxylic acid can be orthogonally protected as known in the art to form an ester. In Step 5 the appropriately substituted and protected alkene is subjected to a carbene to form a bicyclic ring. In Step 6 the appropriately substituted ester is saponified with acid to liberate the carboxylic acid. In Step 7 the appropriately substituted Cbz-protected species is deprotected with hydrogen to liberate the free amine. 
     
       
         
         
             
             
         
       
     
     Scheme 5-2: In Step 1 the appropriately substituted sulfide is oxidized to a sulfoxide as known in the art. Alternatively, in Step 2 the appropriately substituted sulfide is oxidized to a sulfone as known in the art. In Step 3 the appropriately substituted carboxylic acid is coupled to the appropriately substituted amine as known in the art to form an amide. In Step 4 the appropriately substituted Boc-protected species is deprotected with acid to liberate the free amine. 
     
       
         
         
             
             
         
       
     
     Scheme 5-3: In Step 1 the appropriately substituted carboxylic acid is converted to the acyl chloride as known in the art. In Step 2 the appropriately substituted acyl chloride is converted to the Weinreb amide as known in the art. In Step 3 the appropriately substituted Weinreb amide is reacted with a Grignard reagent to afford a ketone. The synthesis of complex Grignard reagents is described in Example 4. In Step 4 the appropriately substituted carbamate protected amine is deprotected to liberate the free amine. 
     
       
         
         
             
             
         
       
     
     Scheme 5-4: In Step 1 the appropriately substituted amide is converted to a thioamide with Lawesson&#39;s reagent. In Step 2 the appropriately substituted Boc-protected amine is deprotected with acid to liberate the free amine. 
     
       
         
         
             
             
         
       
     
     Scheme 5-5: In Step 1 the appropriately substituted carboxylic acid is converted to a Weinreb amide as known in the art. In Step 2 the appropriately substituted Weinreb amide is reduced as known in the art to afford an aldehyde. In Step 3 the appropriately substituted aldehyde is subjected to an amine to form a Schiff base which is subsequently quenched in Step 4. In Step 4 the appropriately substituted Schiff base is subjected to an appropriate nucleophile to form a complex amine. In Step 5 the appropriately substituted Boc-protected species is deprotected with acid to liberate the free amine. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Scheme 5-6: In Step 1 the appropriately substituted alcohol is subjected to TMSCl as known in the art to afford a silyl ether. In Step 2 the appropriately substituted silyl ether is subjected with sodium cyanide to afford a cyano species. In Step 3 the appropriately substituted cyano species is reduced as known in the art to afford an aldehyde. In Step 4 the appropriately substituted aldehyde is further reduced with borane to afford an alcohol. In Step 5 the appropriately substituted alcohol is oxidized as known in the art to afford a carboxylic acid. In Step 6 the appropriately substituted carboxylic acid is coupled to the appropriately substituted amine as known in the art to form an amide. In Step 7 the appropriately substituted ester is converted to a methyl ketone by insitu formation of the Weinreb amide with subsequent attack by the methyl Grignard reagent. In Step 8 the appropriately substituted methyl ketone is subjected to bromine to afford a bromide. By choice of the appropriate starting material all mixtures of chiral centers may be prepared as described. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1: Dimethyl 3-(benzyloxy)pentanedioate (S2) 
     To a solution of Scheme 5-7 compound S1 (24 g, 0.136 mol) and benzyl 2,2,2-trichloroacetimidate (51.3 g, 0.204 mol) in cychexane/dichloromethane (600 mL/120 mL) at room temperature was added trifluoromethanesulfonic anhydride (cat. 1.2 mL) dropwise. The reaction mixture was stirred at room temperature overnight and filtered. The filtrate was washed with sat. NaHCO 3  and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=10:1) to afford the title compound (S2) (35 g, 93.3% yield) as a yellow oil. 
     Step 2: 3-(Benzyloxy)pentane-1,5-diol (S3) 
     To a solution of Scheme 5-7 compound S2 (35 g, 0.13 mol) in THF (anhydrous, 200 mL) was added lithium aluminium hydride (15 g, 0.39 mol) in portions at 0° C. The mixture was heated to 65° C. for 4 h. The mixture was quenched by aqueous sodium hydroxide solution (15 mL, 15% wt) and water (15 mL+45 mL). The slurry was filtered and the filter cake was washed with dichloromethane twice, the combined filtrates were dried over sodium sulfate and concentrated to afford the title compound (S3) (22 g, 79.7% yield) as a yellow oil. 
     Step 3: ((1,5-Dibromopentan-3-yloxy)methyl)benzene (S4) 
     To a mixture of Scheme 5-7 compound S3 (22 g, 0.10 mol) and PPh 3  (82.3 g, 0.31 mol) in dry dichloromethane (200 mL) was added perbromomethane (86.95 g, 0.26 mol) in dry dichloromethane (50 mL) dropwise at 0° C. The reaction was stirred at room temperature overnight and concentrated under reduced pressure to afford a residue, which was purified by silica gel chromatography (petroleum ether:ethyl acetate=80:1) to afford the title compound (S4) (23 g, 66.7% yield) as a yellow oil. 
     Step 4: (2S,5R)-2-(3-(Benzyloxy)-5-bromopentyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (S6) 
     To a dry-ice/acetone cooled solution of Scheme 5-7 compound S5 (5 g, 0.027 mol) in THF (50 ml), was dropwise added n-BuLi (2.5 M, 14.1 mL, 0.035 mol) for 30 min. After addition, the reaction was stirred at this temperature for 30 min followed by dropwise addition of a solution of Scheme 5-7 compound S4 (13.6 g, 0.04 mol) in THF (20 mL). The reaction mixture was stirred at this temperature for another 30 min and allowed to stir at room temperature for 16 h. The reaction was quenched with aq. NH 4 Cl (50 mL) and extracted with ethyl acetate (60 mL×2). The combined organic fractions were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and then concentrated. The residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=10:1) to afford the title compound (S6) (6 g, yield 50.4%) and compound S4 (4.8 g) was recovered. 
     Step 5: (2S)-Methyl 2-amino-5-(benzyloxy)-7-bromoheptanoate hydrochloride (S7) 
     To a mixture of Scheme 5-7 compound S6 (6 g, 0.01 mol) in dioxane (30 mL) was added 0.5 M HCl (30 mL, dropwise at 0° C. The reaction was stirred at room temperature overnight and concentrated under reduced pressure to afford a residue, which was co-evaporated with toluene (15 mL×2) to afford the title compound (S7) (crude hydrochloride, 8 g) as a brown oil. The residue was used directly in the next reaction without purification. 
     Step 6: (2S)-1-tert-Butyl 2-methyl 5-(benzyloxy)azepane-1,2-dicarboxylate (S8) 
     To a mixture of Scheme 5-7 compound S7 (8 g crude) in acetonitrile (80 mL) was added DIPEA (9.03 mL, 0.054 mol), followed by sodium iodide (2.05 g, 0.013 mol). The reaction was stirred at 90° C. for 16 h. The compound (Boc) 2 O (5.97 g, 0.027 mol) was added and the reaction mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with ethyl acetate (100 mL) and washed twice with brine (30 mL×2). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated to afford crude product, which was purified by silica gel chromatography (petroleum ether:ethyl acetate=20:1) to afford the title compound (S8) (3.6 g, 72.4% yield) as a colorless oil. 
     Step 7: tert-Butyl (2S)-1-tert-butyl 2-methyl 5-hydroxyazepane-1,2-dicarboxylate (S9) 
     A solution of Scheme 5-7 compound S8 (1.6 g, 4.40 mmol) and cat. HOAc (1.5 mL) in methanol (35 mL) was degassed three times under a N 2  atmosphere and Pd(OH) 2  (240 mg) was added. The mixture was degassed again and stirred under a H 2  filled balloon at 50° C. over 12 h. The reaction was filtered through Celite®, and the filtrate was concentrated to afford the title compound (S9) (1.1 g, 91.3% yield) as a light yellow oil. 
     Step 8: (2S)-1-tert-Butyl 2-methyl 5-fluoroazepane-1,2-dicarboxylate (S10) 
     To a dry-ice/ethanol cooled solution of Scheme 5-7 compound S9 (1.1 g, 4.03 mmol) in DCM (20 mL) was added DAST (0.79 mL, 6.04 mmol) dropwise. The reaction mixture was warmed up slowly and stirred at room temperature overnight. After quenching with saturated aq.NaHCO 3  solution, the mixture was extracted with DCM (20 mL×2). The combined organic fractions were washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to afford crude product which was purified by silica gel chromatography (petroleum ether:ethyl acetate=10:1) to afford the title compound (S10) (750 mg, 68.1% yield) as a colorless oil. 
     Step 9: (2S)-1-(tert-Butoxycarbonyl)-5-fluoroazepane-2-carboxylic acid (S11) 
     To a mixture of Scheme 5-7 compound S10 (750 mg, 2.72 mmol) in THF (7 mL) was added aq. NaOH solution (4 M, 2.7 mL, 10.8 mmol). The reaction was stirred at 40° C. overnight and concentrated under reduced pressure. The residue was diluted with water (10 mL) and washed with Et 2 O (3 mL×2). The aqueous layer was acidified with diluted hydrochloric acid (1 M) to pH=3. The resulting mixture was extracted with DCM (10 mL×2). The combined organic fractions were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated under reduced pressure to afford the title compound (S11) (700 mg, 98.4% yield) as a white solid. 
     Step 10: (2S)-tert-Butyl 5-fluoro-2-(6-methylpyridin-2-ylcarbamoyl)azepane-1-carboxylate (S12) 
     To a solution of Scheme 5-7 compound S11 (500 mg, 1.91 mmol) and 6-methylpyridin-2-amine (248 mg, 2.29 mmol) in DCE (10 ml) was added DIPEA (0.95 mL, 5.73 mmol) and EEDQ (943.5 mg, 3.82 mmol). The reaction mixture was stirred at 90° C. overnight and concentrated under high vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=10:1) to afford the title compound (S12) (500 mg, 74.4% yield) as a white solid. 
     Step 11: (2S)-5-Fluoro-N-(6-methylpyridin-2-yl)azepane-2-carboxamide hydrochloride (S13) 
     To a mixture of Scheme 5-7 compound S12 (500 mg, 1.42 mmol) in dioxane (2 mL) was added HCl/dioxane (4 M, 5 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to afford Scheme 5-7 compound S13 (550 mg, 100% yield) as a white solid, which was directly used without further purification. 
     
       
         
         
             
             
         
       
     
     Step 1: (2S,4R)-tert-Butyl 4-fluoro-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (S2) 
     To a solution of Scheme 5-8 compound 51 (5 g, 21.43 mmol) in DCM (100 mL) was added N,O-dimethylhydroxylamine hydrochloride (2.5 g, 25.72 mmol), EDCI (6.16 g, 32.14 mmol) and HOBt (2.9 g, 21.43 mmol) followed by TEA (5.4 g, 53.58 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM and washed with water and brine, dried over anhydrous Na 2 SO 4  and concentrated to afford crude product, which was washed with petroleum ether/EtOAc (2/1) to afford the title compound (S2) (5.5 g, 92.88% yield) as a white solid. 
     Step 2: (2S,4R)-tert-Butyl 4-fluoro-2-formylpyrrolidine-1-carboxylate (S3) 
     To a solution of Scheme 5-8 compound S2 (5 g, 18.12 mmol) in THF (40 mL) was added LiAlH 4  (1.38 g, 36.23 mmol). The reaction was stirred at 0° C. for 2 h. The reaction was quenched with water (1.38 mL), aq. NaOH solution (1.38 mL, 15% wt) and water (4 mL) successively. The mixture was filtered and the filter cake was washed with THF twice. The combined filtrates were concentrated to dryness to afford crude product which was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=30:1 to 10:1) to afford the title compound (S3) (2.7 g, 68.7% yield) as a white solid. 
     Step 3: (2S,4R)-tert-Butyl 4-fluoro-2-((R)-1-hydroxy-2-(6-methylpyridin-2-yl)ethyl)pyrrolidine-1-carboxylate (S4) &amp; (2R,4R)-tert-butyl 4-fluoro-2-((S)-1-hydroxy-2-(6-methylpyridin-2-yl)ethyl)pyrrolidine-1-carboxylate (S4A) 
     To a stirred solution of 2,6-dimethylpyridine (2.46 g, 23.04 mmol) in THF (50 mL) was added n-butyllithium (1.6 M in THF, 7.2 mL, 11.52 mmol) dropwise at −70° C. The reaction mixture was stirred at this temperature for 1 h and then Scheme 5-7 compound S3 (2.5 g, 1.52 mmol) in THF (10 mL) was added at −70° C. for 30 min. The mixture was stirred at this temperature for 1 h and quenched with aq. NH 4 Cl solution. The resulting mixture was extracted with EtOAc (100 mL). The organic phase was washed with brine, dried with anhydrous Na 2 SO 4  and concentrated. The residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=20:1 to 10:1) to afford Scheme 5-7 compound S4 (1.2 g, 26.3% yield) and Scheme 5-7 compound S4A (1.3 g, 28.56% yield) as a white solid. 
     Step 4: (R)-1-((2S,4R)-4-Fluoropyrrolidin-2-yl)-2-(6-methylpyridin-2-yl)ethanol (S5) 
     To a solution of compound Scheme 5-8 compound S4 (1.2 g, 3.7 mmol) in dioxane (10 mL) was added HCl/dioxane (4 M, 5 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction solution was concentrated to afford Scheme 5-7 compound S5 (1.3 g, 100% yield) as a white solid which was used directly in the next reaction without purification. 
     Step 5: (5)-1-((2R,4R)-4-Fluoropyrrolidin-2-yl)-2-(6-methylpyridin-2-yl)ethan-1-ol hydrochloride (S6) 
     To a solution of Scheme 5-8 compound S4A (1.3 g, 4 mmol) in dioxane (10 mL) was added HCl/dioxane (4 M, 5 mL). The reaction mixture was stirred at room temperature for 1 h and concentrated to dryness to afford Scheme 5-7 compound S6 (1.4 g, 100% yield) as a white solid which was used without further purification. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1: ((Prop-2-ynyloxy)methyl)benzene (S2) 
     To a solution of Scheme 5-9 compound 51 (15.5 g, 0.277 mol) in dry DMF (150 mL) was added NaH (12 g, 305 mol) at 0° C. slowly. After stirring at 0° C. for 1 h, BnBr (52 g, 305 mol) was added into the above mixture at 0° C. The reaction was stirred at room temperature for 16 h. The mixture was quenched with saturated aq. NH 4 Cl solution (150 mL) and then extracted with DCM (300 mL). The organic layer was washed with aq. LiCl solution (150 mL×3), dried over anhydrous Na 2 SO 4  and concentrated. The residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=100:0 to 100:1) to afford the title compound (S2) (21 g, 53.1% yield) as a colorless oil. 
     Step 2: ((Propa-1,2-dienyloxy)methyl)benzene (S3) 
     To a solution of Scheme 5-9 compound S2 (21 g, 0.144 mol) in dry THF (120 ml) was added t-BuOK (4.84 g, 0.0432 mol). The reaction mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure. Et 2 O (200 mL) was added and the resulting mixture was filtered. The filtrate was concentrated and purified by column chromatography on silica gel (eluted with petroleum ether) to afford the title compound (S3) (13.8 g, 66.3% yield) as a colorless oil. 
     Step 3: (S)-Ethyl 2-aminopent-4-enoate (S5) 
     To a solution of Scheme 5-9 compound S4 (5 g, 43.5 mmol) in EtOH (70 mL) was added SOCl 2  (15.52 g, 130.5 mmol) dropwisely at 0° C. The reaction was stirred at room temperature for 16 h and concentrated. The residue was triturated with Et 2 O (60 mL) and filtered to afford the title compound (7 g, yield 89%) as a white powder, which was used in the next reaction without further purification. LC/MS (ESI) m/z: 144 (M+H) + . 
     Step 4: (S)-Ethyl 2-(4-nitrophenylsulfonamido)pent-4-enoate (S7) 
     To a mixture of Scheme 5-9 compound S5 (7 g, 39 mmol) and TEA (9.85 g, 97.5 mmol) in DCM (80 mL) was added 4-nitrobenzene-1-sulfonyl chloride (8.63 g, 39 mmol). The reaction mixture was stirred at room temperature overnight and then quenched with saturated aq.NaHCO 3  solution (100 mL). The resulting mixture was extracted with DCM (50 mL×2). The combined organic fractions were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and then concentrated. The residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=15:1 to 8:1) to afford the title compound (S7) (9.2 g, 71.84% yield) as a yellow oil. LC/MS (ESI) m/z: 327 (M−H) + . 
     Step 5: (S)-Ethyl 2-(N-(1-(benzyloxy)allyl)-4-nitrophenylsulfonamido)pent-4-enoate (S8) 
     To a solution of Scheme 5-9 compound S7 (8.4 g, 25.6 mmol) in MeCN (90 mL) was added ((propa-1,2-dienyloxy)methyl)benzene (4.2 g, 28.17 mmol), DPPP (1.06 g, 2.56 mmol), TEA (5.17 g, 51.2 mmol) and Pd(OAc) 2  (576 mg, 2.56 mmol). The reaction was degassed and stirred at room temperature for 16 h under N 2  atmosphere. The mixture was concentrated to dryness and the residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=30:1 to 20:1) to afford the title compound (S8) (8.1 g, 66.67% yield) as a yellow solid. 
     Step 6: (S)-Ethyl 6-(benzyloxy)-1-(4-nitrophenylsulfonyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (S9) 
     To a solution of Scheme 5-9 compound S8 (8 g, 16.88 mmol) in dry degassed toluene (80 mL) was added Grubbs I catalyst (707 mg, 0.844 mmol) under a N 2  atmosphere. The resulting mixture was degassed three times and stirred at 80° C. for 20 h under a N 2  atmosphere. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=15:1 to 6:1) to afford the title compound (S9) (6.58 g, 87.31% yield) as a yellow oil. LC/MS (ESI) m/z: 447 (M−H) + . 
     Step 7: (S)-Ethyl 1-(4-nitrophenylsulfonyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (S10) 
     To a mixture of Scheme 5-9 compound S9 (6.58 g, 14.72 mmol) and triethylsilane (5.17 g, 44.16 mmol) in dry DCM (80 mL) was added boron trifluoride etherate (6.27 g, 44.16 mmol) at −75° C. under a N 2  atmosphere dropwise. The reaction was stirred at −75° C. for 1 h and then at room temperature for 3 h. The mixture was quenched with saturated NaHCO 3  solution (100 mL) and extracted with DCM (60 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=15:1 to 8:1) to afford the title compound (S10) (4.5 g, 89.8% yield) as a colorless oil. 
     Step 8: (5)-1-(4-Nitrophenylsulfonyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid (S11) 
     To a mixture of Scheme 5-9 compound S10 (4.5 g, 13.22 mmol) in EtOH/THF/H 2 O (40 mL, 1:2:1, V/V) was added LiOH (1.66 g, 39.66 mmol). The reaction mixture was stirred at room temperature for 4 h and then acidified with aq. HCl solution (1 M) to pH=5. The resulting mixture was extracted with DCM/MeOH (40 mL×2, 20:1, V/V). The combined organic fractions were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to afford the title compound (3.3 g, 79.9% yield) as a yellow solid, which was directly used in the next reaction without further purification. LC/MS (ESI) m/z: 311 (M−H) + . 
     Step 9: (S)—N-(6-Methylpyridin-2-yl)-1-(4-nitrophenylsulfonyl)-1,2,3,6-tetrahydropyridine-2-carboxamide (S12) 
     To a solution of Scheme 5-9 compound S11 (1.77 g, 5.76 mmol) in dichloroethane (30 mL) was added 6-methylpyridin-2-amine (674 mg, 6.24 mmol), EEDQ (2.82 g, 11.34 mmol) and DIPEA (2.22 g, 17 mmol). The reaction was heated at reflux overnight under a N 2  atmosphere. After cooling, the mixture was concentrated and purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=8:1 to 2:1) to afford the title compound (S12) (1.4 g, 60.4% yield) as a yellow solid. LC/MS (ESI) m/z: 403 (M+H) + . 
     Step 10: (S)—N-(6-Methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-2-carboxamide (S13) 
     To a solution of Scheme 5-9 compound S12 (740 mg, 1.84 mmol) in DMF (8 mL) was added K 2 CO 3  (762 mg, 5.52 mmol) and 4-methoxybenzenethiol (335 mg, 2.4 mmol). The reaction was stirred at room temperature for 24 h. Then the mixture was diluted with a 10% LiCl solution (40 ml) and extracted with DCM/MeOH (40 mL×2, 20:1, V/V). The combined organic fractions were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with DCM:MeOH=100:0 to 50:1) to afford Scheme 5-9 compound S13 (310 mg, 77.54% yield) as a yellow solid. LC/MS (ESI) m/z: 218 (M+H) + . 
     Example 6. Synthesis of a Moieties 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Scheme 6-1: In Step 1 the appropriately substituted nitro species is reduced with palladium as known in the art to afford an amine. In Step 2 the appropriately substituted alkene species is brominated with concurrent addition of ethanol as known in the art to afford the bromide species. In Step 3 the appropriately substituted mixture of tautomers is subjected to the previously prepared bromide species as known in the art to afford the two isomers. The appropriately substituted isomers corresponding to each tautomer may either be separated or used as a mixture in the subsequent reactions with separation at a later step. In Step 4 the appropriately substituted ketal species is deprotected and subsequently cyclized in the presence of acid as known in the art. In Step 5 the appropriately substituted cyano species is subjected to strong acid to afford a primary amide. In Step 6 the appropriately substituted heterocycle is subjected to a bromide species of the appropriate linker to afford the appropriately protected species. Various 5-5 fused bicyclic systems can be appropriately prepared by slight modifications of this synthetic protocol, another non-limiting example is presented in Steps 5 through 12 with the same conditions for formation of a primary amide and installation of linker. In Step 7 the appropriately substituted aryl species is brominated as known in the art. In Step 8 the appropriately substituted ether species is deprotected with palladium as known in the art to afford an alcohol. In Step 9 the appropriately substituted alcohol is oxidized as known in the art to afford an aldehyde. In Step 10 the appropriately substituted aldehyde is subjected to hydrazine to first form a Schiff base and subsequently cyclize to afford a bicyclic system. In Step 11 the appropriately substituted bicyclic system is iodinated as known in the art. In Step 12 the appropriately substituted iodide is subjected to sodium cyanide to afford the cyano species. 
     
       
         
         
             
             
         
       
     
     Scheme 6-2: Non-limiting examples of amide substituents are provided demonstrating the robust nature of the synthetic protocol. Nucleophiles 1-5 are subjected to an appropriately substituted isocyanate to afford various species. In Step 1 the appropriately substituted isocyanate species can simply be prepared as known in the art. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Scheme 6-3: In Step 1 the appropriately substituted bromide is subjected to magnesium as known in the art to afford a Grignard reagent. In Step 2 the appropriately substituted Grignard reagent is subjected to gaseous or solid carbon dioxide to afford a carboxylic acid. In Step 3 the appropriately substituted aryl species is iodinated as known in the art to afford an iodide species. In Step 4 the appropriately substituted iodide is subjected to cyanide to afford a cyano species. In Step 5 the appropriately substituted cyano species is subjected to strong acid to afford an amide. In Step 6 the appropriately substituted heterocycle is subjected to a bromide species of the appropriate linker to afford the appropriately protected species. In Step 7 the appropriately substituted carboxylic acid is converted to various amides as known in the art. In Step 8 the appropriately substituted ester is converted to a carboxylic acid in the presence of TFA. 
     
       
         
         
             
             
         
       
     
     Scheme 6-4: In Step 1 the appropriately substituted and protected aniline is converted as known in the art to a sulfonamide. In Step 2 the appropriately substituted alcohol is converted as known in the art to a triflouro sulfonamide. In Step 3 the previously prepared reagents are subjected to sodium hydride to afford their adduct. In Step 4 the appropriately substituted ketal is subjected to a strong lewis acid to afford deprotection and subsequent cyclization to a biaryl species. In Step 5 the appropriately substituted sulfonamide is deprotected in the presence of base to afford a free amine. In an alternative embodiment this synthetic protocol can be applied to other aniline isomers to afford substituents on alternative positions. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Scheme 6-5: In Step 1 the appropriately substituted indole is acylated as known in the art. In Step 2 the appropriately substituted heterocycle is subjected to a bromide species of the appropriate linker to afford the appropriately protected species. In Step 3 the appropriately substituted aryl bromide is converted to an isocyanate as known in the art. In Step 4 the appropriately substituted isocyanate is subjected to an amine to afford a urea species. In Step 5 the appropriately substituted benzyl alcohol is deprotected in the presence of hydrogen gas and palladium to afford a free alcohol. In Step 6 the appropriately substituted phenol is subjected to a sulfonic anhydride to afford a leaving group. In Step 7 the appropriately substituted aryl species is converted to a boronic acid as known in the art. In Step 8 the appropriately substituted boronic acid is subjected to copper bromide to afford an aryl bromide species. In an alternative embodiment this synthetic protocol can simply be applied to other indole isomers to afford substituents on alternative positions. 
     
       
         
         
             
             
         
       
     
     Scheme 6-6: Non-limiting examples of amide substituents are provided demonstrating the robust nature of the synthetic protocol. Nucleophiles 1-5 are subjected to an appropriately substituted isocyanate to afford various species. In Step 1 the appropriately substituted isocyanate species can simply be prepared as known in the art. 
     Example 7. Synthesis of L3-A Moieties 
     
       
         
         
             
             
         
       
     
     Scheme 7-1: In Step 1 the appropriately substituted aryl compound is subjected to a bromide to afford a sulfonic acid substituted species. In Step 2 the appropriately substituted sulfonic acid species is chlorinated as known in the art. 
     
       
         
         
             
             
         
       
     
     Scheme 7-2: In Step 1 the appropriately substituted aryl compound is subjected to a chloride to afford a phosphonic acid substituted species. In Step 2 the appropriately substituted phosphonic acid species is chlorinated as known in the art. 
     Example 8. Coupling of L3-A to C-L-B 
     
       
         
         
             
             
         
       
     
     Scheme 8-1: In Step 1 the appropriately substituted amine is subjected to a sulfonyl chloride which can be prepared as described in Scheme 7-1 to afford a compound of Formula I. 
     
       
         
         
             
             
         
       
     
     Scheme 8-2: In Step 1 the appropriately substituted amine is subjected to a phosphonic dichloride which can be prepared as described in Scheme 7-2 followed by a subsequent quench with water to afford a compound of Formula I. 
     
       
         
         
             
             
         
       
     
     Scheme 8-3: In Step 1 the appropriately substituted oxetane is subjected to conditions known in the art to form an amino/cyano substituted species. In Step 2 the appropriately substituted cyano species is reduced as known in the art to afford an aldehyde. In Step 3 the appropriately substituted aldehyde is reduced with borane to afford an alcohol. In Step 4 the appropriately substituted alcohol is converted to a bromide as known in the art. In Step 5 the appropriately substituted bromide is subjected to a heteroaryl species as known in the art to afford a compound of Formula I. 
     
       
         
         
             
             
         
       
     
     Scheme 8-4: In Step 1 the appropriately substituted bromide is subjected to a heteroaryl species to afford a compound of Formula I. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Scheme 8-5: In Step 1 the appropriately substituted carboxylic acid is coupled to the appropriately substituted amine as known in the art to form a compound of Formula I. 
     Example 9. Synthesis of Amide Compounds of Formula I, Formula I′ and Formula I″ Synthesis of (S)-(1-(3-carbamoyl-1-(2-(2-(2-(3-chloro-2-fluorophenyl)acetyl)-4-oxoazetidin-1-yl)-2-oxoethyl)-1H-indazole-5-carbonyl)piperidin-4-yl)boronic acid (S15) 
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Scheme 9-1 
     Step 1: Ethyl 3-iodo-1H-indazole-5-carboxylate (S2) 
     To a solution of Scheme 9-1 compound 51 (1 equiv) in DMF (20 vol) at 0° C. is added iodine (1.5 equiv) and potassium hydroxide (2.5 equiv). The reaction mixture is stirred at room temperature for 3 h and then quenched with 10% aqueous sodium thiosulfate solution. The resulting mixture is extracted with ethyl acetate. The organic layer is separated, dried over anhydrous Na 2 SO 4 , filtered and then concentrated. The residue is purified by column chromatography on silica gel to afford Scheme 9-1 compound S2. 
     Step 2: Ethyl 3-cyano-1H-indazole-5-carboxylate (S3) 
     To a mixture of Scheme 9-1 compound S2 (1 equiv) and Zn(CN) 2  (1.1 equiv) in DMF (10 vol) and water (1 vol) is added Pd (dppf)Cl 2  (0.1 equiv) and Pd 2 (dba) 3  (0.1 equiv). The reaction mixture is stirred at 80° C. for 3 h and then cooled to room temperature. Water is added to the reaction mixture and the resulting mixture is extracted with ethyl acetate. The organic layer is separated, dried over anhydrous Na 2 SO 4 , filtered and then concentrated. The residue is purified by column chromatography on silica gel to afford Scheme 9-1 compound S3. 
     Step 3: Ethyl 1-(2-(tert-butoxy)-2-oxoethyl)-3-cyano-1H-indazole-5-carboxylate (S4) 
     To a solution of Scheme 9-1 compound S3 (1 equiv) and potassium carbonate (1.1 equiv) in DMF (10 vol) is added tert-butyl bromoacetate (1.1 equiv). The reaction mixture is stirred at 60° C. for 3 h and then quenched with water. The resulting mixture is extracted with ethyl acetate. The organic layer is separated, dried over anhydrous Na 2 SO 4 , filtered and then concentrated. The residue is purified by column chromatography on silica gel to afford Scheme 9-1 compound S4. 
     Step 4: Ethyl 1-(2-(tert-butoxy)-2-oxoethyl)-3-carbamoyl-1H-indazole-5-carboxylate (S5) 
     To a solution of Scheme 9-1 compound S4 (1 equiv) in ethanol/water (10 vol, 1:4) is added acetaldoxime (2 equiv), palladiumacetate (0.05 equiv) and triphenylphoshpine (0.1 equiv). The reaction mixture is stirred at 80° C. for 3 h and then cooled to room temperature. The reaction mixture is filtered through Celite and the filtrate is concentrated. The residue is purified by column chromatography on silica gel to afford Scheme 9-1 compound S5. 
     Step 5: 2-(3-Carbamoyl-5-(ethoxycarbonyl)-1H-indazol-1-yl)acetic acid (S6) 
     To a solution of Scheme 9-1 compound S5 (1 equiv) in DCM (10 vol) is added TFA (5 vol). The reaction mixture is stirred at 50° C. for 3 h and then concentrated. The residue is re-crystallized from MTBE to afford Scheme 9-1 compound S6. 
     Scheme 9-2 
     Step 1: (5)-1-(tert-Butoxycarbonyl)-4-oxoazetidine-2-carboxylic acid (S8) 
     To a solution of Scheme 9-2 compound S7 (1 equiv) and 2 M NaOH (2 equiv) in THF (10 vol) at 0° C. is added Boc anhydride (1.2 equiv). The reaction mixture is stirred at room temperature for 16 h and then quenched with 1 M HCl. The resulting mixture is extracted with ethyl acetate. The organic layer is separated, dried over anhydrous Na 2 SO 4 , filtered and then concentrated. The residue is re-crystallized from MTBE to afford Scheme 9-2 compound S8. 
     Step 2: tert-Butyl (S)-2-(methoxy(methyl)carbamoyl)-4-oxoazetidine-1-carboxylate (S9) 
     To a solution of Scheme 9-2 compound S8 (1 equiv) in DMF (10 vol) at 0° C. is added N,O-dimethyl hydroxylamine (1.2 equiv), N-(3-Dimethylaminopropyl)-N′-ethylcabodiimidehydrochloride (2 equiv) and HOBt (1.2 equiv). The reaction mixture is stirred at room temperature for 16 h and then quenched with water. The resulting mixture is extracted with ethyl acetate. The organic layer is separated, dried over anhydrous Na 2 SO 4 , filtered and then concentrated. The residue is purified by column chromatography on silica gel to afford Scheme 9-2 compound S9. 
     Step 3: tert-Butyl (S)-2-(2-(3-chloro-2-fluorophenyl)acetyl)-4-oxoazetidine-1-carboxylate (S10) 
     To a mixture (3-chloro-2-fluorobenzyl) magnesium bromide (1 equiv) in THF at −78° C. under nitrogen protection is added a solution of Scheme 9-2 compound S9 (1 equiv) in THF (10 vol). After addition, the mixture is stirred at −78° C. for 1 h and then quenched with saturated aqueous ammonium chloride solution. The organic layer is washed with brine, dried over anhydrous Na 2 SO 4 , filtered and then concentrated. The residue is purified by column chromatography on silica gel to afford Scheme 9-2 compound S10. 
     Step 4: (S)-4-(2-(3-Chloro-2-fluorophenyl)acetyl)azetidin-2-one (S11) 
     To a solution of Scheme 9-2 compound S10 (1 equiv) in 1,4-dioxane (2 vol) at 0° C. is added 4 N HCl in dioxane (10 vol). The reaction mixture is stirred at room temperature for 6 h and then concentrated. The residue is taken in MTBE and stirred for 30 min. The resultant solid is filtered and dried to afford Scheme 9-2 compound 511. 
     Step 5: Ethyl (S)-3-carbamoyl-1-(2-(2-(2-(3-chloro-2-fluorophenyl)acetyl)-4-oxoazetidin-1-yl)-2-oxoethyl)-1H-indazole-5-carboxylate (S12) 
     To a solution of Scheme 9-2 compound S11 (1 equiv) and compound S6 (1.2 equiv) in DMF (10 vol) 0° C. is added DIPEA (2 equiv) and HATU (1.2 equiv). The reaction mixture is stirred at room temperature for 16 h and then quenched with water. The resultant solid is filtered, washed with MTBE to afford Scheme 9-2 compound S12. 
     Step 6: (S)-3-Carbamoyl-1-(2-(2-(2-(3-chloro-2-fluorophenyl)acetyl)-4-oxoazetidin-1-yl)-2-oxoethyl)-1H-indazole-5-carboxylic acid (S13) 
     To a solution of Scheme 9-2 compound S12 (1 equiv) in THF/water (8:2) is added LiOH (4 equiv). The reaction mixture is stirred at room temperature for 4 h and then quenched with 1 M citric acid. The resulting mixture is extracted with ethyl acetate. The organic layer is separated, dried over anhydrous Na 2 SO 4 , filtered and then concentrated. The residue is re-crystallized from MTBE to afford Scheme 9-2 compound S13. 
     Step 7: (S)-1-(2-(2-(2-(3-Chloro-2-fluorophenyl)acetyl)-4-oxoazetidin-1-yl)-2-oxoethyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidine-1-carbonyl)-1H-indazole-3-carboxamide (S14) 
     To a solution of Scheme 9-2 compound S13 (1 equiv) and compound S6 (1.2 equiv) in DMF (10 vol) 0° C. is added DIPEA (2 equiv) and HATU (1.2 equiv). The reaction mixture is stirred at room temperature for 16 h and then quenched with water. The resulting mixture is extracted with ethyl acetate. The organic layer is separated, dried over anhydrous Na 2 SO 4 , filtered and then concentrated. The residue is re-crystallized from MTBE to afford Scheme 9-2 compound S14. 
     Step 14: (S)-(1-(3-Carbamoyl-1-(2-(2-(2-(3-chloro-2-fluorophenyl)acetyl)-4-oxoazetidin-1-yl)-2-oxoethyl)-1H-indazole-5-carbonyl)piperidin-4-yl)boronic acid (S15) 
     To a solution of Scheme 9-2 compound S14 in acetone/water (2:0.2) is added sodium periodate (3 equiv) and 1 N ammonium acetate (10 vol). The reaction mixture is stirred at room temperature for 20 h and then quenched with water. The resulting mixture is extracted with ethyl acetate. The organic layer is separated, washed with 1 N HCl, dried over anhydrous Na 2 SO 4 , filtered and then concentrated. The residue is purified by column chromatography on silica gel to afford Scheme 9-2 compound S15. 
     Synthesis of (5)-1-(((2-((6-Bromopyridin-2-yl)carbamoyl)-3,6-dihydropyridin-1(2H)-yl)sulfonyl)methyl)-5-(3-(isoxazol-3-ylmethyl)ureido)-1H-indole-3-carboxamide (S11) 
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Scheme 9-3 
     Step 1: 1-(tert-Butyl) 5-methyl 1H-indole-1,5-dicarboxylate (S2) 
     To a solution of Scheme 9-3 compound 51 (1 equiv) and DMAP (0.1 equiv) in DCM (10 vol) is added Boc anhydride (1.2 equiv). The reaction mixture is stirred at room temperature for 16 h and then quenched with water. The resulting mixture is extracted with DCM. The organic layer is separated, dried over anhydrous Na 2 SO 4 , filtered and then concentrated. The residue is purified by column chromatography on silica gel to afford Scheme 9-3 compound S2. 
     Step 2: 1-(tert-Butyl) 5-methyl 3-carbamoyl-1H-indole-1,5-dicarboxylate (S3) 
     To a solution of Scheme 9-3 compound S2 (1 equiv) in acetonitrile (2 vol) at 0° C. is added chlorosulfonyl isocyanate (1.5 equiv). The reaction mixture is stirred at room temperature for 2 h and then quenched with a mixture of acetone (1.5 vol) and water (0.2 vol). This solution is basified with 10% KOH and extracted with ethyl acetate. The organic layer is separated, dried over anhydrous Na 2 SO 4 , filtered and then concentrated to afford Scheme 9-3 compound S3. 
     Step 3: Methyl 3-carbamoyl-1H-indole-5-carboxylate (S4) 
     To a solution of Scheme 9-3 compound S3 (1 equiv) in DCM (10 vol) at 0° C. is added TFA (5 vol). The reaction mixture is stirred at 50° C. for 3 h and then concentrated. The residue is re-crystallized from MTBE to afford Scheme 9-3 compound S4. 
     Scheme 9-4 
     Step 1: (5)-1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid (S6) 
     To a solution of Scheme 9-4 compound S5 (1 equiv) and 2 M NaOH (2 equiv) in THF (10 vol) at 0° C. is added Boc anhydride (1.2 equiv). The reaction mixture is stirred at room temperature for 16 h and then quenched 1 M HCl. The resulting mixture is extracted with ethyl acetate. The organic layer is separated, dried over anhydrous Na 2 SO 4 , filtered and then concentrated. The residue is re-crystallized from MTBE to afford Scheme 9-4 compound S6. 
     Step 2: (S)—N-(6-Bromopyridin-2-yl)-1,2,3,6-tetrahydropyridine-2-carboxamide (S7) 
     To a solution of Scheme 9-4 compound S6 (1 equiv) and 6-bromopyridin-2-amine (1.2 equiv) in DMF (10 vol) at 0° C. is added DIPEA (2 equiv) and HATU (1.2 equiv). The reaction mixture is stirred at room temperature for 16 h and then quenched with water. The resulting mixture is extracted with ethyl acetate. The organic layer is separated, dried over anhydrous Na 2 SO 4 , filtered and then concentrated. The residue is purified by column chromatography on silica gel to afford Scheme 9-4 compound S7. 
     Step 3: (S)—N-(6-Bromopyridin-2-yl)-1-((chloromethyl)sulfonyl)-1,2,3,6-tetrahydropyridine-2-carboxamide (S8) 
     To a solution of Scheme 9-4 compound S7 (1 equiv) in DCM (2 vol) at 0° C. is added chloromethanesulfonylchloride (1.2 equiv). The reaction mixture is stirred at room temperature for 3 h and then quenched with water. The resulting mixture is extracted with DCM. The organic layer is separated, dried over anhydrous Na 2 SO 4 , filtered and then concentrated to afford Scheme 9-4 compound S8. 
     Step 4: Methyl(S)-1-(((2-((6-bromopyridin-2-yl)carbamoyl)-3,6-dihydropyridin-1(2H)-yl)sulfonyl)methyl)-3-carbamoyl-1H-indole-5-carboxylate (S9) 
     To a solution of Scheme 9-4 compound S8 (1 equiv) and compound 4 (1.2 equiv) in DMF (10 vol) is added potassium carbonate (3 equiv). The reaction mixture is stirred at 80° C. for 2 h and then quenched with water. The resulting mixture is extracted with ethyl acetate. The organic layer is separated, dried over anhydrous Na 2 SO 4 , filtered and then concentrated. The residue is purified by column chromatography on silica gel to afford Scheme 9-4 compound S9. 
     Step 5: (5)-1-(((2-((6-Bromopyridin-2-yl)carbamoyl)-3,6-dihydropyridin-1(2H)-yl)sulfonyl)methyl)-3-carbamoyl-1H-indole-5-carboxylic acid (S10) 
     To a solution of Scheme 9-4 compound S9 (1 equiv) in THF/water (8:2) is added LiOH (4 equiv). The reaction mixture is stirred at room temperature for 4 h and then quenched with 1 M citric acid. The resulting mixture is extracted with ethyl acetate. The organic layer is separated, dried over anhydrous Na 2 SO 4 , filtered and then concentrated. The residue is re-crystallized from MTBE to afford Scheme 9-4 compound S10. 
     Step 6: (5)-1-(((2-((6-Bromopyridin-2-yl)carbamoyl)-3,6-dihydropyridin-1(2H)-yl)sulfonyl) methyl)-5-(3-(isoxazol-3-ylmethyl)ureido)-1H-indole-3-carboxamide (S11) 
     To a solution of Scheme 9-4 compound S10 (1.2 equiv) and triethylamine (1.5 equiv) in benzene (10 vol) is added DPPA (1.2 equiv). The reaction mixture is stirred at 80° C. for 2 h and then cooled to room temperature. Then triethylamine (8 equiv) and isoxazol-3-ylmethanamine (4 equiv) are added into the above reaction mixture at room temperature. The reaction mixture is heated at 80° C. for 2 h and then quenched with water. The resulting mixture is extracted with ethyl acetate. The organic layer is separated, dried over anhydrous Na 2 SO 4 , filtered and then concentrated. The residue is purified by column chromatography on silica gel to afford Scheme 9-4 compound 511. 
     
       
         
         
             
             
         
       
     
     A mixture of 2-(3-carbamoyl-5-((cyclopropyl sulfonyl)carbamoyl)-1H-indol-1-yl)acetic acid (30 mg, 0.082 mmol), (R)-1-((2R,4R)-4-fluoropyrrolidin-2-yl)-2-(6-methyl pyridin-2-yl)ethanol (30.4 mg, 0.086 mmol), HATU (46.7 mmol, 0.123 mmol) and DIPEA (0.04 mL, 0.246 mmol) in DMF (2 mL) is stirred at room temperature overnight. The mixture is partitioned with EtOAc (10 mL) and water (20 mL). The aqueous layer is washed with EtOAc twice and concentrated to afford crude product, which is purified by preparative HPLC to afford the desired product (6) (5 mg, 10.7% yield) as a white solid.  1 H NMR (600 MHz, CD 3 OD) δ 8.74 (s, 1H), 8.35 (t, J=8.0 Hz, 1H), 7.98 (s, 1H), 7.81-7.73 (m, 3H), 7.51 (d, J=8.7 Hz, 1H), 5.52 (s, 1H), 5.37 (d, J=17.5 Hz, 1H), 5.16 (d, J=17.4 Hz, 1H), 4.53 (d, J=10.0 Hz, 1H), 4.38 (t, J=7.7 Hz, 1H), 4.19 (dd, J=20.2, 12.8 Hz, 1H), 3.85-3.75 (m, 1H), 3.19 (td, J=8.0, 4.0 Hz, 1H), 3.13 (dd, J=14.0, 3.0 Hz, 1H), 2.90 (dd, J=14.0, 10.4 Hz, 1H), 2.75 (s, 3H), 2.61-2.50 (m, 1H), 2.38 (m, 1H), 1.36-1.31 (m, 2H), 1.16 (dd, J=7.8, 2.2 Hz, 2H). LC/MS (ESI) m/z: 572 [M+H] + . 
     
       
         
         
             
             
         
       
     
     The titled compound (7) is prepared according the procedure for the synthesis of N5-(cyclopropylsulfonyl)-1-(2-((2R,4R)-4-fluoro-2-((R)-1-hydroxy-2-(6-methylpyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-3,5-dicarboxamide (6).  1 H NMR (400 MHz, CD 3 OD) δ 8.76 (d, J=5.5 Hz, 1H), 8.35 (t, J=7.9 Hz, 1H), 8.01 (m, 1H), 7.76 (m, 3H), 7.57 (d, J=8.7 Hz, 1H), 5.58-5.28 (m, 3H), 4.59 (s, 1H), 4.29-4.10 (m, 2H), 3.90 (m, 1H), 3.22-3.12 (m, 2H), 2.97 (m, 1H), 2.83 (s, 1H), 2.74 (d, J=10.1 Hz, 2H), 2.53-2.31 (m, 2H), 1.33 (d, J=2.4 Hz, 2H), 1.16 (d, J=5.6 Hz, 2H). LC/MS (ESI) m/z: 572 [M+H] + . 
     
       
         
         
             
             
         
       
     
     The titled compound (5) is prepared according to the procedure for the synthesis of N5-(cyclopropylsulfonyl)-1-(2-((2R,4R)-4-fluoro-2-((R)-1-hydroxy-2-(6-methylpyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-3,5-dicarboxamide (6).  1 H NMR (400 MHz, CD3OD) δ 8.76 (s, 1H), 8.01 (s, 1H), 7.92-7.79 (m, 2H), 7.67 (t, J=7.9 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.03 (m, 1H), 6.00-5.85 (m, 2H), 5.45 (m, 3H), 4.42 (s, 2H), 3.23-3.14 (m, 1H), 2.85-2.75 (m, 1H), 2.68 (s, 1H), 2.48 (d, J=11.4 Hz, 3H), 1.33 (dd, J=4.5, 2.5 Hz, 2H), 1.20-1.10 (m, 2H). LC/MS (ESI) m/z: 565 [M+H] + . 
     
       
         
         
             
             
         
       
     
     The titled compound (8) is prepared according to the procedure for the synthesis of N5-(cyclopropylsulfonyl)-1-(2-((2R,4R)-4-fluoro-2-((R)-1-hydroxy-2-(6-methylpyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-3,5-dicarboxamide (6).  1 H NMR (400 MHz, CD3OD) δ 8.72 (d, J=1.4 Hz, 1H), 7.98 (s, 1H), 7.84-7.73 (m, 2H), 7.65-7.58 (m, 1H), 7.50 (d, J=8.7 Hz, 1H), 6.96 (d, J=7.5 Hz, 1H), 5.51 (d, J=17.3 Hz, 1H), 5.34 (d, J=17.2 Hz, 1H), 4.62 (m, 1H), 4.00 (d, J=16.9 Hz, 1H), 3.60 (dd, J=16.1, 11.8 Hz, 1H), 3.17 (m, 1H), 2.41 (s, 3H), 2.38-2.10 (m, 3H), 2.04-1.69 (m, 4H), 1.30 (dd, J=4.6, 2.3 Hz, 2H), 1.12 (dd, J=7.9, 2.3 Hz, 2H). LC/MS (ESI) m/z: 599 [M+H] + . 
     Example 10. Synthesis of Compounds of Formula I′ 
     
       
         
         
             
             
         
       
     
     Scheme 10-1: In Step 1 the appropriately substituted bromide is subjected to a phthalimide to afford a protected alkene species. In Step 2 the appropriately substituted phthalimide-protected amine is subjected to hydrazine as known in the art to afford a free amine. In Step 3 the two appropriately substituted species previously prepared react as known in the art to afford a terminal alkene species. In Step 4 the appropriately substituted ester is treated with TFA to afford a carboxylic acid. In Step 5 the appropriately substituted carboxylic acid is converted to an amide as known in the art. In Step 6 the di-alkene species is cyclized as known in the art to form a macrocyclic species. In Step 7 the appropriately substituted macrocyclic-alkene species is reduced with hydrogen to afford a macrocyclic-alkyl species. 
     Example 11. Non-Limiting Examples of Amide Compounds of Formula I 
     In the illustrative compounds in  FIG.  16   , and elsewhere herein, R 32  is depicted as Z 32 , which are intended to be the same moieties. 
     Example 12. Human Factor D Assay 
     Human Factor D (purified from human serum, Complement Technology, Inc.) at 80 nM final concentration is incubated with test compound at various concentrations for 5 minutes at room temperature in 50 mM Tris, 1M NaCl, pH 7.5. A synthetic substrate Z-L-Lys-SBzl and DTNB (Ellman&#39;s reagent) are added to final concentrations of 100 μM each. Absorbance at 405 nm (A 405 ) is recorded at 30 second intervals for 30 minutes using a microplate spectrophotometer. IC 50  values are calculated by nonlinear regression of complement Factor D reaction rates as a function of test compound concentration. 
     Example 13. Hemolysis Assay 
     The hemolysis assay was previously described by G. Ruiz-Gomez, et al., J. Med. Chem. (2009) 52: 6042-6052. Prior to the assay, the optimum concentration of Normal Human Serum (NETS) needed to achieve 100% lysis of rabbit erythrocytes (RE) is determined by titration. In the assay, NETS (Complement Technology) is diluted in GVB 0  Buffer (0.1% gelatin, 5 mM Veronal, 145 mM NaCl, 0.025% NaN 3 , pH 7.3, Complement Technology) plus 10 mM Mg-EGTA and incubated with test compound at various concentrations for 15 minutes at 37° C. RE (Complement Technology) freshly suspended in GVB 0 plus 10 mM Mg-EGTA are added to a final concentration of 1×10 8  cells/mL and reactions are incubated for 30 minutes at 37° C. Positive control reactions (100% lysis) consist of GVB 0 plus 10 mM Mg-EGTA with NETS and RE but without test compound; negative control reactions (0% lysis) consist of GVB 0 plus 10 mM Mg-EGTA with RE only. Samples are centrifuged at 2000 g for 3 minutes and supernatants collected. Absorbance at 405 nm (A 405 ) is recorded using a microplate spectrophotometer. IC 50  values are calculated by nonlinear regression from the percentage of hemolysis as a function of test compound concentration. 
     Example 14. Non-Limiting Examples of Compounds of Formula I 
     Table 3 shows illustrative compounds of Formula I with characterizing data. The assay of Example 12 was used to determine the IC 50 &#39;s of the compounds. Other standard Factor D inhibition assays are also available. Three ***s are used to denote compounds with an IC 50  less than 1 micromolar; two **s indicate compound with an IC 50  between 1 micromolar and 10 micromolar, and one * denotes compounds with an IC 50  greater than 10 micromolar. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Non-limiting Examples of Compounds of Formula I 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 RT min 
                   
               
               
                 Cmp 
                   
                   
                   
                 (Method 
                 MS 
               
               
                 No. 
                 Structure 
                 Name 
                 IC 50   
                 A or B) 
                 (M + 1) 
               
               
                   
               
               
                 1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (S)-5-(3,3- difluoropiperidine- 1-carboxamido)-1- (2-(6-((6- methylpyridin-2- yl)carbamoyl)-5,6- dihydropyridin- 1(2H)-yl)-2- oxoethyl)-1H- indole-3- carboxamide  
                 * 
                 2.12 (B) 
                 580 
               
               
                   
               
               
                 2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 5-(3,3- difluoropiperidine- 1-carboxamido)-1- (2-((2R,4R)-4- fluoro-2-((R)-1- hydroxy-2-(6- methylpyridin-2- yl)ethyl)pyrrolidin- 1-yl)-2-oxoethyl)- 1H-indole-3- carboxamide 
                 * 
                 0.73 (B) 
                 587 
               
               
                   
               
               
                 3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 5-(3,3- difluoropiperidine- 1-carboxamido)-1- (2-((2S,4R)-4- fluoro-2-((S)-1- hydroxy-2-(6- methylpyridin-2- yl)ethyl)pyrrolidin- 1-yl)-2-oxoethyl)- 1H-indole-3- carboxamide  
                 * 
                 1.20 (B) 
                 587 
               
               
                   
               
               
                 4 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 5-(3,3- difluoropiperidine- 1-carboxamido)-1- (2-((2S)-5-fluoro-2- ((6-methylpyridin- 2- yl)carbamoyl)azepan- 1-yl)-2- oxoethyl)-1H- indole-3- carboxamide  
                 * 
                 3.30 (B) 
                 614 
               
               
                   
               
               
                 5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (S)-N5- (cyclopropylsulfonyl)- 1-(2-(6-((6- methylpyridin-2- yl)carbamoyl)-5,6- dihydropyridin- 1(2H)-yl)-2- oxoethyl)-1H- indole-3,5- dicarboxamide  
                 * 
                 1.95 (B) 
                 565 
               
               
                   
               
               
                 6 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N5- (cyclopropylsulfonyl)- 1-(2-((2R,4R)- 4-fluoro-2-((R)-1- hydroxy-2-(6- methylpyridin-2- yl)ethyl)pyrrolidin- 1-yl)-2-oxoethyl)- 1H-indole-3,5- dicarboxamide 
                 * 
                 2.82 (B) 
                 572 
               
               
                   
               
               
                 7 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N5- (cyclopropylsulfonyl)- 1-(2-((2S,4R)-4- fluoro-2-((S)-1- hydroxy-2-(6- methylpyridin-2- yl)ethyl)pyrrolidin- 1-yl)-2-oxoethyl)- 1H-indole-3,5- dicarboxamide  
                 * 
                 2.82 (B) 
                 572 
               
               
                   
               
               
                 8 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N5- (cyclopropylsulfonyl)- 1-(2-((2S)-5- fluoro-2-((6- methylpyridin-2- yl)carbamoyl)azepan- 1-yl)-2- oxoethyl)-1H- indole-3,5- dicarboxamide 
                 * 
                 3.64 (B) 
                 599 
               
               
                   
               
            
           
         
       
     
     This specification has been described with reference to embodiments of the invention. However, one of ordinary skill in the art appreciates that various modifications and changes can be made without departing from the scope of the invention as set forth in the claims below. Accordingly, the specification is to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of invention.