Classifications

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  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
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  • A61K31/401—Proline; Derivatives thereof, e.g. captopril
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  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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  • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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  • A61K31/415—1,2-Diazoles
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  • A61K31/4164—1,3-Diazoles
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  • A61K31/4164—1,3-Diazoles
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Definitions

• the complement system is a part of the innate immune system which does not adapt to changes over the course of the host'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 phaogytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cell lysis (rupturing membranes of foreign cells) and agglutination (clustering and binding of pathogens together).
• 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 0), which associates with factor B to form the C3(H 2 0)B complex.
• Complement factor D acts to cleave factor B within the C3(H 2 0)B complex to form Ba and Bb.
• the Bb fragment remains associated with C3(H 2 0) to form the alternative pathway C3 convertase C3(H 2 0)Bb.
• 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.
• complement pathway 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.
• disorders mediated by the complement pathway include age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis, and rheumatoid arthritis.
• ASD Age-related macular degeneration
• Paroxysmal nocturnal hemoglobinuria 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.
• the anti-C5 monoclonal antibody eculizumab has been approved in the U.S. for treatment of PNH.
• many of the patients treated with eculizumab remain anemic, and many patients continue to require blood transfusions.
• 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.
• factor D inhibitors 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.
• Novartis PCT patent publications WO2014/002057 titled “Pyrrolidine derivatives and their use as complement pathway modulators” and WO2014/009833 titled “Complement pathway modulators and uses thereof describe additional factor D inhibitors with heterocyclic substituents. Additional factor D inhibitors are described in Novartis PCT patent publications WO2014/002051, WO2014/002052, WO2014/002053, WO2014/002054, WO2014/002058, WO2014/002059, and WO2014/005150.
• Japan Tobacco Inc. PCT patent publication WO 1999/048492 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.
• PCT patent publication WO 1993/020099 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 WO 1995/029697 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's anti-C5 antibody eculizumab Soliris®
• Soliris® is currently the only complement-specific antibody on the market, and is the first and only approved treatment for paroxysmal nocturnal hemoglobinuria (PNH).
• the present 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, is a superior inhibitor of complement factor D.
• a method for the treatment of a disorder associated with a dysfunction, including increased activity, of the complement pathway includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, as described in more detail below.
• the disorder is associated with the alternative complement cascade pathway.
• the disorder is associated with the complement classical pathway.
• the disorder is associated with the complement lectin pathway.
• the factor D inhibitors provided herein can thus dampen or inhibit detrimental complement activity in a host, by administration of an effective amount in a suitable manner to a host in need thereof.
• a method for the treatment of paroxysmal nocturnal hemoglobinuria includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
• a method for the treatment of age-related macular degeneration is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
• a method for the treatment of rheumatoid arthritis includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
• a method for the treatment of multiple sclerosis includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
• 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 C3 amplification loop of the complement pathway.
• 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.
• Part A The disclosure below is considered Part A of the specification. Part B is provided further below, which is an incorporation by explicit reference of the terms of the priority documents for this specification.
• Q 1 is N(R J ) or QRV);
• Q 2 is C(R 2 Pv 2' ), C(R 2 R 2' )-C(R 2 R 2' ), S, O, N(R 2 ) or C(R 2 R 2' )0;
• Q 3 is N(R 3 ), S, or C(R 3 R 3' );
• R and R' are independently chosen 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.
• 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 mixtrues 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.
• Z is F, CI, 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 chosen at each occurrence, as appropriate, and only where a stable compound results, from hydrogen, halogen, hydroxyl, nitro, cyano, amino, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 alkoxy, C 2 -C 6 alkynyl, C 2 - C 6 alkanoyl, Ci-Cethioalkyl, hydroxyCi-C 6 alkyl, aminoCi-Cealkyl, -Co-C 4 alkylNR 9 R 10 , -C(0)OR 9 , -OC(0)R 9 , -NR 9 C(0)R 10 , -C(0)NR 9 R 10 , -OC(0)NR 9 R 10 , -NR 9 C(0)OR 10 , Ci- C 2 haloalkyl, and Ci-C 2 hal
• 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 chosen 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 chosen from halogen (and in particular F), hydroxyl, cyano, -COOH, Ci-C 4 alkyl (including in particular methyl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, Ci-C 4 alkoxy, C 2 -C 4 alkanoyl,
• 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 chosen 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 chosen from halogen (and in particular F), hydroxyl, cyano, -COOH, Ci-C 4 alkyl (including in particular methyl), C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, Ci-C 4 alkoxy, C 2
• R and R , R and R , or R and R can be taken together to form a carbonyl group.
• R 1 and R 2 or R 2 and R 3 can be taken together to form a carbon-carbon double bond.
• A is a group chosen from:
• R 4 is chosen from -CHO, -CONH 2 , C 2 -C 6 alkanoyl, hydrogen, -S0 2 NH 2 , -C(CH 2 ) 2 F, -CH(CF 3 )NH 2 , Ci-C 6 alkyl, -Co-C 4 alkyl(C 3 -C 7 cycloalkyl), -C(O)C 0 -C 2 alkyl(C 3 - C 7 cycloalkyl),
• each of which R 4 other than hydrogen, -CHO, and -CONH 2 is unsubstituted or substituted with one or more of amino, imino, halogen, hydroxyl, cyano, cyanoimino, Ci-C 2 alkyl, Ci-C 2 alkoxy, -Co-C 2 alkyl(mono- and di-Ci-C 4 alkylamino), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
• R 5 and R 6 are independently chosen from -CHO, -C(0)NH 2 , -C(0)NH(CH 3 ), C 2 - C 6 alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, -COOH, -S0 2 NH 2 , vinyl, Ci-C 6 alkyl (including methyl), C 2 -C 6 alkenyl, Ci-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(0)(OR 9 ) 2 , -OC(0)R 9 , -C(0)OR 9 , -C(0)N(CH 2 CH 2 R 9 )(R 10 ), -NR 9 C(0)R 10 , phenyl, or 5- to 6-membered heteroaryl.
• R 5 and R 6 other than hydrogen, hydroxyl, cyano, and -COOH is unsubstituted or optionally substituted.
• R 5 and R 6 other than hydrogen, hydroxyl, cyano, and -COOH may be substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, imino, cyano, cyanoimino, Ci-C 2 alkyl, Ci-C 4 alkoxy, -Co- C 2 alkyl(mono- and di-Ci-C 4 alkylamino), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
• R 6 is hydrogen, halogen, hydroxyl, Ci-C 4 alkyl, -Co-C 4 alkyl(C 3 -Cycycloalkyl), or Ci-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, Ci-C 6 alkyl, or -Co-C 4 alkyl(C 3 -C 7 cycloalkyl).
• R 8 and R 8 are independently chosen from hydrogen, halogen, hydroxyl, Ci- C 6 alkyl, -Co-C 4 alkyl(C 3 -C 7 cycloalkyl), Ci-C 6 alkoxy, and (Ci-C 4 alkylamino)Co-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 may include one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, Ci-C 6 alkoxy, -C 0 - C 4 alkyl(mono- and di-Ci-Cealkylamino), -Co-C 4 alkyl(C 3 -C 7 cycloalkyl), Ci-C 2 haloalkyl, and Ci- C 2 haloalkoxy.
• substituents independently chosen from halogen, hydroxyl, nitro, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, Ci-C 6 alkoxy, -C 0 - C 4 alkyl(mono- and di-Ci-Cealkylamino), -Co-C 4 alkyl(C 3 -C 7
• R 19 is hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, -S0 2 Ci-C 6 alkyl, (mono- and di-Ci-C 6 alkylamino)Ci-C 4 alkyl, -Co-C 4 alkyl(C 3 -C 7 cycloalkyl), -Co-C 4 alkyl(C 3 - C 7 heterocycloalkyl), -Co-C 4 alkyl(aryl), Co-C 4 alkyl(heteroaryl), and wherein R 19 other than hydrogen is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, -COOH, and -C(0)OCi-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 .
• R and R is chosen from R and the other of R and R is chosen from
• R 31 is chosen from hydrogen, halogen, hydroxyl, nitro, cyano, amino, -COOH, Ci- C 2 haloalkyl, Ci-C 2 haloalkoxy, Ci-C 6 alkyl, -Co-C 4 alkyl(C 3 -C 7 cycloalkyl), C 2 -C 6 alkenyl, C 2 - C 6 alkanoyl, Ci-C 6 alkoxy, C 2 -C 6 alkenyloxy, -C(0)OR 9 , Ci-C 6 thioalkyl, -C 0 -C 4 alkylNR 9 R 10 , -C(0)NR 9 R 10 , -SO 2 R 9 , -S0 2 NR 9 R 10 , -OC(0)R 9 , and -C(NR 9 )NR 9 R 10 each of which R 31 other than hydrogen, halogen, hydroxyl, nitro, cyano, Ci-C 2 haloalkyl, and Ci-
• R 32 is chosen from C(0)NR 21 R 37 , -C(0)NR 24 R 25 , -C(0)NR 9 R 37 , -C(0)NR 21 S0 2 R 22 , -NR 9 C(0)OR 10 , -NR 9 C(0)OR 23 , -NR 9 C(0)R 21 , -NR 9 C(0)NR 9 R 10 , -NR 9 C(O)NR 10 R 23 , and -NR 9 C(0)NR 24 R 25 , each of which is optionally substituted;
• R 12 and R 13 are each independently selected from an R 32 moiety.
• R 32 is C(0)NR 21 R 37 , -C(0)NR 24 R 25 , -C(0)NR 9 R 37 , B is not C 2 -C 6 alkenyl; (C0-C4 alkyl)(heteroaryl); monocyclic or bicyclic carbocyclic; or monocyclic heterocyclic.
• R 11 , R 14 , and R 15 are independently chosen at each occurrence from hydrogen, halogen, hydroxyl, nitro, cyano, -0(PO)(OR 9 ) 2 , -(PO)(OR 9 ) 2 , Ci-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, Ci
• R 21 and R 22 are independently chosen at each occurrence from hydrogen, hydroxyl, cyano, amino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, (C 3 -C 7 cycloalkyl)Co-C 4 alkyl, (phenyl)C 0 -C 4 alkyl, -Ci-C 4 alkylOC(0)OCi-C 6 alkyl, -C C 4 alkylOC(0)Ci-C 6 alkyl, -C C 4 alkylC(0)OCi-C 6 alkyl, (4- to 7-membered heterocycloalkyl)Co-C 4 alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6- membered unsaturated or aromatic heterocycle)Co-C 4 alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and each R 21 and R 22 can be optionally substituted.
• R 23 is independently chosen at each occurrence from Ci-C 6 alkyl, Ci-C 6 haloalkyl, (C 3 -C 7 cycloalkyl)Co-C 4 alkyl, (aryl)Co-C 4 alkyl, (4- to 7-membered heterocycloalkyl)Co-C 4 alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6- membered unsaturated or aromatic heterocycle)Co-C 4 alkyl having 1 , 2, or 3 heteroatoms independently chosen from N, O, and S.
• 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.
• R 37 is chosen at each occurrence from hydroxyl, Ci-C 6 alkoxy, (C 3 - C 7 cycloalkyl)Co-C 4 alkyl, (phenyl)C 0 -C 4 alkyl, -Ci-C 4 alkylOC(0)OCi-C 6 alkyl, -Ci- C 4 alkylOC(0)Ci-C 6 alkyl, -Ci-C 4 alkylC(0)OCi-C 6 alkyl, (4- to 7-membered heterocycloalkyl)C 0 - C 4 alkyl having 1 , 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6- membered unsaturated or aromatic heterocycle)Co-C 4 alkyl having 1 , 2, or 3 heteroatoms independently chosen from N, O, and S, and each can be optionally substituted.
• L is a bond or is chosen from the formulas
• R 17 is hydrogen, Ci-C 6 alkyl, or -Co-C 4 alkyl(C3-C 7 cycloalkyl) and R 18 and R 18 are independently chosen from hydrogen, halogen, hydroxymethyl, and methyl; and m is 0, 1 , 2, or
• B 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) .
• R 33 is independently chosen from halogen, hydroxyl, -COOH, cyano, Ci-C 6 alkyl, C 2 -C 6 alkanoyl, Ci-C 6 alkoxy, -C 0 -C 4 alkylNR 9 R 10 , -S0 2 R 9 , Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy;
• R 34 is independently chosen from nitro, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci- Cethioalkyl, -JC 3 -C 7 cycloalkyl, -B(OH) 2 , -JC(0)NR 9 R 23 ,-JOS0 2 OR 21 , -C(0)(CH 2 )i_ 4 S(0)R 21 , -0(CH 2 )i_ 4 S(0)NR 21 R 22 -JOP(0)(OR 21 )(OR 22 ), -JP(0)(OR 21 )(OR 22 ), -JOP(0)(OR 21 )R 22 , -JP(0)(OR 21 )R 22 , -JOP(0)R 21 R 22 , -JP(0)R 21 R 22 , -JSP(0)(OR 21 )(OR 22 ), -JSP(0)(OR 21 )(R 22 ), -JSP(0)(OR 21 )(R 22 ), -JSP(0)(R 21 )
• R may be unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH) 2 , -Si(CH 3 ) 3 , -COOH, -CONH 2 , -P(0)(OH) 2 , Ci-C 6 alkyl, -C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), Ci-C 6 alkoxy, -Co-C 2 alkyl(mono- and di-Ci-C 4 alkylamino), Ci-C 6 alkylester, Ci-C 4 alkylamino, Ci-C 4 hydroxylalkyl, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
• R 35 is independently chosen from naphthyl, naphthyloxy, indanyl, (4- to 7- membered heterocycloalkyl)Co-C 4 alkyl containing 1 or 2 heteroatoms chosen from N, O, and S, and bicyclic heterocycle containing 1 , 2, or 3 heteroatoms independently chosen 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 chosen from halogen, hydroxyl, nitro, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, Ci-C 6 alkoxy, (mono- and di-Ci- C 6 alkylamino)Co-C 4 alkyl, C C 6 alkylester, -C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), -S0 2
• R 36 is independently chosen from tetrazolyl, (phenyl)Co-C 2 alkyl, (phenyl)Ci- C 2 alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing 1 , 2, or 3 heteroatoms independently chosen from N, O, B, and S, each of which R 36 is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, Ci-C 6 alkoxy, (mono- and di-Ci-C 6 alkylamino)Co-C 4 alkyl, Ci- C 6 alkylester, -C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), -S0 2 R 9 , -OSi(CH 3 ) 2 C(CH 3 ) 3 , -Si(
• J is independently chosen at each occurrence from a covalent bond, Ci- C 4 alkylene, -OCi-C 4 alkylene, C 2 -C 4 alkenylene, and C 2 -C 4 alkynylene.
• compositions comprising a compound or salt of Formula I together with a pharmaceutically acceptable carrier are also disclosed.
• methods of treating or preventing disorders mediated by complement cascade factor D including but not limited to age-related macular degeneration (AMD), retinal degeneration, other ophthalmic diseases (e.g., geographic atrophy), paroxysymal nocturnal hemoglobinuria (PNH), multiple sclerosis (MS), arthritis including rheumatoid arthritis (RA), a respiratory disease or a cardiovascular disease, are provided, comprising administering a therapeutically effective amount of a compound or salt of Formula I to a host, including a human, in need of such treatment are also disclosed.
• AMD age-related macular degeneration
• PNH paroxysymal nocturnal hemoglobinuria
• MS multiple sclerosis
• RA rheumatoid arthritis
• a respiratory disease or a cardiovascular disease comprising administering a therapeutically effective amount of a compound or salt of Formula I to a host, including
• an effective amount of an active factor D inhibiting compound is provided to treat an inflammatory or immune disorder, including an autoimmune disorder, that is meadited or affected by factor D.
• an inflammatory or immune disorder including an autoimmune disorder, that is meadited or affected by factor D.
• the compound of Formula I can be used to treat a disorder mediated by the complement pathway, regardless whether it is acting through Factor D.
• the present invention includes at least the following features:
• cascade factor D including age-related macular degeneration (AMD), retinal degeneration, paroxysymal nocturnal hemoglobinuria (PNH), multiple sclerosis (MS), and rheumatoid arthritis (RA) and other disorders described further herein;
• a process for manufacturing a medicament intended for the therapeutic use for treating or preventing treating or preventing disorders mediated by complement cascade factor D including age-related macular degeneration (AMD), retinal degeneration, paroxysymal nocturnal hemoglobinuria (PNH), multiple sclerosis (MS), and rheumatoid arthritis (RA) and other disorders described further herein characterized in that Formula I as described herein is used in the manufacture;
• AMD age-related macular degeneration
• PNH paroxysymal nocturnal hemoglobinuria
• MS multiple sclerosis
• RA rheumatoid arthritis
• 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.
• "Formula I” includes all subgeneric groups of Formula I, such as Formula IA and Formula IB and also includes pharmaceutically acceptable salts of a compound of Formula I, unless clearly contraindicated by the context in which this phrase is used.
• Forma I also includes all subgeneric groups of Formula I, such as Formulas IC - ID, and Formulas II - XXX, and also includes pharmaceutically acceptable salts of all subgeneric groups of Formula I, such as Formulas IA - ID, and Formulas II - XXX, unless contraindicated by the context in which this phrase is used.
• the present invention includes compounds of Formula I and the use of compounds 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.
• 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, U C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 CI, 125 I respectively.
• the invention includes isotopically modified compounds of Formula I.
• 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.
• PET positron emission tomography
• SPECT single-photon emission computed tomography
• an 18 F 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.
• isotopes of hydrogen for example, deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in described structures that achieves the desired result.
• isotopes of carbon e.g., 13 C and 14 C, may be used.
• 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.
• the deuterium can be bound to carbon in a location of bond breakage during metabolism (an a-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a ⁇ -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.
• 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.
• the substitution of a hydrogen atom for a deuterium atom occurs within an R group substituent on the L-B moiety region. In one embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within an R group selected from any of R 18 , R 18' , R 33 , R 34 , R 35 , and/or R 36. In one embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within an R group substituent within the A-carbonyl moiety region.
• the substitution of a hydrogen atom for a deuterium atom occurs at 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 30 , and/or R 30a .
• certain substituents on the proline ring are selectively deuterated.
• the substitution of a hydrogen atom for a deuterium atom occurs at
• R, R , R , R , R , R% R" , R ⁇ and/or R J when any of the R substituents of the proline ring are methyl or methoxy, the alkyl residue is optionally deuterated, e.g., CD 3 or OCD 3 . In certain other embodiments, when two substituents of the proline ring are combined to form a cyclopropyl ring, the unsubstituted methylene carbon is deuterated.
• substitution of a hydrogen atom for a deuterium atom occurs within an R group when at least one of the variables within the R group is hydrogen (e.g., 2 H or D) or alkyl (e.g., CD 3 ).
• the alkyl residue is typically deuterated, e.g., CD 3, CH 2 CD 3 or CD 2 CD 3 .
• 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.
• solvate refers to a molecular complex of a compound of the present invention (including salts thereof) with one or more solvent molecules. Examples of solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents.
• 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 0, d 6 -acetone, d6-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.
• substituted 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's normal valence is not exceeded.
• an oxo group replaces two hydrogens in an aromatic moiety, the corresponding partially unsaturated ring replaces the aromatic ring.
• a pyridyl group substituted by oxo is a pyridone.
• a stable compound or stable structure refers to a compound leading to a compound that can be isolated and can be formulated into a dosage form with a shelf life of at least one month.
• Any suitable group may be present on a "substituted” or “optionally substituted” position that forms a stable molecule and advances the desired purpose of the invention and includes, but is not limited to, e.g., halogen (which can independently be F, CI, Br or I); cyano; hydroxyl; nitro; azido; alkanoyl (such as a C 2 -C6 alkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; alkylthio including those having one or more thioether linkages; alkylsulfmyl; 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
• "optionally substituted” includes one or more substituents independently chosen from halogen, hydroxyl, amino, cyano, -CHO, -COOH, -CONH 2 , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -C C 6 alkoxy, C 2 -C 6 alkanoyl, Ci-Cealkylester, (mono- and di-Ci-C 6 alkylamino)Co-C 2 alkyl, Ci- C 2 haloalkyl, hydoxyCi-C 6 alkyl, ester, carbamate, urea, sulfonamide,-Ci-C6alkyl(heterocyclo), Ci-C 6 alkyl(heteroaryl), -Ci-C 6 alkyl(C 3 -C 7 cycloalkyl), 0-C
• 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 Ci-C 2 , Ci-C 3 , or Ci-C 6 .
• the specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species.
• Ci-C 6 alkyl 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.
• Ci- C 4 alkyl 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.
• Co-C n alkyl is used herein in conjunction with another group, for example, (C 3 _ C 7 cycloalkyl)Co-C 4 alkyl, or -Co-C 4 alkyl(C 3 -C 7 cycloalkyl), the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (Coalkyl), 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 -0-Co-C 4 alkyl(C 3 -C 7 cycloalkyl).
• alkyl examples 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 and 2,3-dimethylbutane.
• the alkyl group is optionally substituted as described above.
• 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, C2-C 6 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.
• 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 -Cgalkynyl 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.
• alkynyl examples 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.
• the alkynyl group is optionally substituted as described above.
• Alkylene is a bivalent saturated hydrocarbon.
• Alkylenes for example, can be a 1 to 8 carbon moiety, 1 to 6 carbon moiety, or an indicated number of carbon atoms, for example Ci-C 4 alkylene, Ci-C 3 alkylene, or Ci-C 2 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 (-0-).
• 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.
• 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 (-0-).
• Alkylester is an alkyl group as defined herein covalently bound through an ester linkage.
• Amide or "carboxamide” is -C(0)NR a R b wherein R a and R b are each independently selected from hydrogen, alkyl, for example, Ci-C 6 alkyl, alkenyl, for example, C 2 - C 6 alkenyl, alkynyl, for example, C 2 -C 6 alkynyl, -Co-C 4 alkyl(C3-C 7 cycloalkyl), -C 0 -C 4 alkyl(C 3 - C 7 heterocycloalkyl), -Co-C 4 alkyl(aryl), and -Co-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.
• the R a and R b groups are each independently optionally substituted as described above.
• Carbocyclic group 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.
• carbocyclic rings examples include cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl and cyclopropyl rings.
• the carbocyclic ring is optionally substituted as described above.
• the cycloalkyl is a partially unsaturated (i.e., not aromatic) group containing all carbon ring atoms.
• 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, -0-, 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.
• 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 subsitutuent.
• aminoalkyl is an alkyl group as previously described, substituted with at least one amino subsitutuent.
• Halo or "halogen” indicates independently any of fluoro, chloro, bromo, and iodo.
• Aryl indicates aromatic groups containing only carbon in the aromatic ring or rings.
• the aryl groups contain 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 chosen 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.
• 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.
• heterocycle 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 radical of 3 to about 12, and more typically 3, 5, 6, 7 to 10 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, 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, and S) or a bicycle having 6 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), for example: a bicyclo [4,5], [5,5], [5,6], or [6,6] system.
• the only heteroatom is nitrogen.
• the only heteroatom is oxygen.
• the only heteroatom is sulfur.
• Heterocycles are described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W. A.
• 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, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2- pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl,
• Spiro moieties are also included within the scope of this definition.
• the heterocycle groups herein are optionally substituted independently with one or more substituents described herein.
• Heterocyclicoxy group is a monocyclic heterocyclic ring or a bicyclic heterocyclic group as described previously linked to the group it substitutes via an oxygen, -0-, linker.
• Heteroaryl indicates a stable monocyclic aromatic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5- to 7- membered aromatic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon.
• the only heteroatom is nitrogen.
• the only heteroatom is oxygen.
• the only heteroatom is sulfur.
• Monocyclic heteroaryl groups typically have from 5 to 7 ring atoms.
• bicyclic heteroaryl groups are 9- to 10-membered heteroaryl groups, that is, groups containing 9 or 10 ring atoms in which one 5- to 7-member aromatic ring is fused to a second aromatic or non-aromatic ring.
• the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another.
• the total number of S and O atoms in the heteroaryl group is not more than 2.
• the total number of S and O atoms in the aromatic heterocycle is not more than 1.
• 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, puriny
• Heterocycloalkyl is a saturated ring group. It may have, for example, 1, 2, 3, or 4 heteroatoms independently chosen from N, S, and O, with remaining ring atoms being carbon. In a typical embodiment, nitrogen is the heteroatm. 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.
• mono- and/ or di-alkylamino indicates secondary or tertiary alkylamino groups, wherein the alkyl groups are independently chosen alkyl groups, as defined herein.
• the point of attachment of the alkylamino group is on the nitrogen.
• mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino.
• a "dosage form” means a unit of administration of an active agent.
• 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, such as a compound or salt of Formula I, 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.
• “Pharmaceutically acceptable salts” includes derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, nontoxic, 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.
• 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.
• conventional nontoxic 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. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th
• 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, and includes, in one embodiment, an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
• a "pharmaceutically acceptable excipient” as used in the present application includes both one and more than one such excipient.
• a "patient” or “host” or “subject” is a human or non-human animal in need of modulation of the complement factor D pathway. Typically the host is a human.
• a “patient” or “host” or “subject” also refers to for example, mammals, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds 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.
• the term "parent drug” means any of the presently described chemical compounds that are useful to treat any of the disorders described herein, or to control or improve the underlying cause or symptoms associated with any physiological or pathological disorder described herein in a host, typically a human.
• 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 of Formula I with at least one additional active agent means the compound of Formula I 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 separated by some amount of time that is within the time in which both the compound of Formula I and the at least one additional active agent are within the blood stream of a patient.
• the compound of Formula I and the additional active agent need not be prescribed for a patient by the same medical care worker.
• the additional active agent or agents need not require a prescription.
• a "therapeutically effective amount" of a pharmaceutical composition/combination of this invention means an amount effective, when administered to a patient, to provide a therapeutic benefit such as an amelioration of symptoms, e.g., an amount effective to decrease the symptoms of a macular degeneration.
• 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's blood, serum, or tissues.
• Non- limiting examples of compounds falling within Formula I with variations in the variables e.g., A, B, R J -R 3 , and L, are illustrated below. The disclosure includes all combinations of these definitions so long as a stable compound results.
• the disclosure includes compounds and salts of Formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX and XXXXX which are within the scope of Formula I.
• the variables shown in Formula II-XXX carry the definitions set forth in the SUMMARY section for Formula I or any of the definitions set forth in this disclosure.
• n 0 or 1.
• the disclosure includes compounds and salts of Formula I and pharmaceutically acceptable compositions thereof, and any of its subformulae (II-XXX) in which at least one of the following conditions is met in the embodiments described below.
• R and R is chosen from R and the other of R and R is chosen from
• R 32 In another embodiment each of R 12 and R 13 can be independently selected from R 32.
• R 31 is chosen from hydrogen, halogen, hydroxyl, nitro, cyano, amino, -COOH, Ci- C 2 haloalkyl, Ci-C 2 haloalkoxy, Ci-C 6 alkyl, -Co-C 4 alkyl(C 3 -C 7 cycloalkyl), C 2 -C 6 alkenyl, C 2 - C 6 alkanoyl, Ci-C 6 alkoxy, C 2 -C 6 alkenyloxy, -C(0)OR 9 , Ci-C 6 thioalkyl, -C 0 -C 4 alkylNR 9 R 10 , -C(0)NR 9 R 10 , -S0 2 R 9 , -S0 2 NR 9 R 10 , -OC(0)R 9 , and -C(NR 9 )NR 9 R 10 each of which R 31 other than hydrogen, halogen, hydroxyl
• R 32 is chosen from C(0)NR 21 R 37 , -C(0)NR 24 R 25 , -C(0)NR 9 R 37 , -C(0)NR 21 S0 2 R 22 , -NR 9 C(0)OR 10 , -NR 9 C(0)OR 23 , -NR 9 C(0)R 21 , -NR 9 C(0)NR 9 R 10 , -NR 9 C(O)NR 10 R 23 , and -NR 9 C(0)NR 24 R 25 , each of which is optionally substituted.
• R 32 is C(0)NR 21 R 37 , -C(0)NR 24 R 25 , -C(0)NR 9 R 37 , B is not C 2 -C 6 alkenyl; (C 0 -C 4 alkyl)(heteroaryl); monocyclic or bicyclic carbocyclic; or monocyclic heterocyclic.
• R is selected from:
• R 12 is R 32 .
• R 12 is R 32 , which is -C(0)NR 21 R 37 .
• R 12 is R 32 , which is -C(0)NR 24 R 25 .
• R 12 is R 32 , which is -C(0)NR 9 R 37 .
• R 12 is R 32 , which is -C(0)NR 21 S0 2 R 22 .
• R 12 is R 32 , which is -NR 9 C(0)OR 10 .
• R 12 is R 32 , which is -NR 9 C(0)OR 23 .
• R 12 is R 32 , which is -NR 9 C(0)R 21 .
• R 12 is R 32 , which is -NR 9 C(0)NR 9 R 10 .
• R 12 is R 32 , which is -NR 9 C(O)NR 10 R 23 .
• R 12 is R 32 , which is -NR 9 C(0)NR 24 R 25 .
• R 32 which is -C(0)NR 21 R 37 .
• R 32 which is -C(0)NR 24 R 25 .
• R 32 which is -C(0)NR 9 R 37 .
• R 32 which is -C(0)NR 21 S0 2 R 22 .
• R 32 which is -NR 9 C(0)OR 10 .
• R 32 which is -NR 9 C(0)OR 23 .
• R 32 which is -NR 9 C(0)R 21 .
• R 32 which is -NR 9 C(0)NR 9 R 10 .
• R 32 which is -NR 9 C(O)NR 10 R 23 .
• R 32 which is -NR 9 C(0)NR 24 R 25 .
• the disclosure provides compounds of I one of R 12 and R 13 is H and the other of R 12 and R 13 is R 32 ,where: [0154] R 32 is chosen from C(0)NR 21 R 37 ,-C(0)NR 24 R 25 , -C(0)NR 9 R 37 , -C(0)NR 21 S0 2 R 22 , -NR 9 C(0)OR 10 , -NR 9 C(0)OR 23 , -NR 9 C(0)R 21 , -NR 9 C(0)NR 9 R 10 , -NR 9 C(O)NR 10 R 23 , and -NR 9 C(0)NR 24 R 25 , each of which is optionally substituted;
• R 9 , R 10 , R 21 , R 22 , R 23 , R 24 , R 25 , and R 37 are as defined in the summary section above.
• the disclosure provides compounds of Formula I, wherein;
• R 1 , R 1 ', R 2 , and R 3' are all hydrogen;
• R 2 is fluoro and R 3 is hydrogen, -Co-C 4 alkyl(C3-C 7 cycloalkyl), or -O-C 0 - C 4 alkyl(C 3 -C 7 cycloalkyl);
• R 5 is hydrogen, halogen, or Ci-C 2 alkyl
• R 11 , R 13 , R 14 , and R 15 are independently chosen at each occurrence from hydrogen, halogen, hydroxyl, amino, Ci-C 4 alkyl, Ci-C 4 alkoxy, -Co-C 2 alkyl(mono- and di- Ci-C 2 alkylamino), trifluoromethyl, and trifluoromethoxy;
• X 12 is CR 12 ;
• R 12 is chosen from C(0)NR 21 R 37 ,-C(0)NR 24 R 25 , -C(0)NR 9 R 37 , -C(0)NR 21 S0 2 R 22 , -NR 9 C(0)OR 10 , -NR 9 C(0)OR 23 , -NR 9 C(0)R 21 , -NR 9 C(0)NR 9 R 10 , -NR 9 C(O)NR 10 R 23 , and -NR 9 C(0)NR 24 R 25 , each of which is optionally substituted;
• R 9 , R 10 , R 21 , R 22 , R 23 , R 24 , R 25 , and R 37 are as defined in the summary section above.
• R 32 is C(0)NR 21 R 37 , -C(0)NR 24 R 25 , -C(0)NR 9 R 37 , B is not C 2 -C 6 alkenyl; (Co-C 4 alkyl)(heteroaryl); monocyclic or bicyclic carbocyclic; or monocyclic heterocyclic.
• the disclosure provides compounds of Formula I, wherein;
• m is O or 1;
• R 2 is halogen
• R 2 is hydrogen or halogen
• R 3 is hydrogen, halogen, -Co- C 4 alkyl(C 3 -C 7 cycloalkyl), or -O-C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl);
• R 6 is -C(0)Ci-C 4 alkyl, -C(0)NH 2 , -C(0)CF 3 , -C(0)(C 3 -C 7 cycloalkyl), or -ethyl(cyanoimino);
• R 12 and R 13 is selected from hydrogen, halogen, Ci-C 4 alkyl, Ci-C 4 alkoxy,
• R 32 is chosen from C(0)NR 21 R 37 ,-C(0)NR 24 R 25 , -C(0)NR 9 R 37 , -C(0)NR 21 S0 2 R 22 , -NR 9 C(0)OR 10 , -NR 9 C(0)OR 23 , -NR 9 C(0)R 21 , -NR 9 C(0)NR 9 R 10 , -NR 9 C(O)NR 10 R 23 , and -NR 9 C(0)NR 24 R 25 , each of which is optionally substituted;
• R 9 , R 10 , R 21 , R 22 , R 23 , R 24 , R 25 , and R 37 are as defined in the summary section above.
• the disclosure provides compounds of Formula I, wherein;
• R 12 and R 13 are hydrogen, hydroxyl, halogen, methyl, or methoxy; and the other of R 12 and R 13 is R 32 , where
• R 32 is chosen from C(0)NR 21 R 37 ,-C(0)NR 24 R 25 , -C(0)NR 9 R 37 , -C(0)NR 21 S0 2 R 22 , -NR 9 C(0)OR 10 , -NR 9 C(0)OR 23 , -NR 9 C(0)R 21 , -NR 9 C(0)NR 9 R 10 , -NR 9 C(O)NR 10 R 23 , and -NR 9 C(0)NR 24 R 25 , each of which is optionally substituted;
• R 9 , R 10 , R 21 , R 22 , R 23 , R 24 , R 25 , and R 37 are as defined in the summary section above.
• R 32 may be unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH) 2 , -Si(CH 3 ) 3 , -COOH, -CONH 2 , -P(0)(OH) 2 , Ci-C 6 alkyl, Ci-C 6 alkoxy, -C 0 -C 2 alkyl(mono- and di- Ci-C 4 alkylamino), Ci-Cealkylester, Ci-C 4 alkylamino, Ci-C 4 hydroxylalkyl, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
• substituents independently chosen from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH) 2 , -Si(CH 3 ) 3 , -COOH, -CONH 2 , -P(0)(
• Q 1 is N(R J ) or QRV);
• 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' )0;
• Q3 is N(R3), S, or C(R3R3');
• R and R' are independently chosen from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl wherein each group can be optionally substituted or any other substituent group herein that provides the desired properties.
• 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 mixtrues 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.
• Z is F, CI, NH 2 , CH 3 , CH 2 D, CHD 2 , or CD 3 .
• R , R , R , R , and R are independently chosen at each occurrence, as appropriate, and only where a stable compound results, from hydrogen, halogen, hydroxyl, nitro, cyano, amino, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 alkoxy, C 2 -C 6 alkynyl, C 2 - C 6 alkanoyl, Ci-Cethioalkyl, hydroxyCi-C 6 alkyl, aminoCi-Cealkyl, -Co-C 4 alkylNR 9 R 10 , -C(0)OR 9 , -OC(0)R 9 , -NR 9 C(0)R 10 , -C(0)NR 9 R 10 , -OC(0)NR 9 R 10 , -NR 9 C(0)OR 10 , C C 2 haloalkyl, and Ci-C 2 haloalkoxy, where R 9 and R 10 are
• 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 chosen 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 one or more substituents independently chosen from halogen (and in particular F), hydroxyl, cyano, -COOH, Ci-C 4 alkyl (including in particular methyl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, Ci-C 4 alkoxy, C 2 - C 4 alkanoyl, hydroxyCi-C 4 alkyl, (mono- and di-Ci-C 4 alkylamino)Co-C 4 alkyl, -Co-C 4 alkyl(C 3 - Cycycloalkyl), -0-Co-C 4 alkyl(C 3 -Cycycloalkyl), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
• substituents independently chosen from halogen (and in particular F), hydroxyl, cyano, -COOH, Ci-C 4 alkyl (including in particular methyl), C
• 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 chosen 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 one or more substituents independently chosen from halogen (and in particular F), hydroxyl, cyano, -COOH, Ci-C 4 alkyl (including in particular methyl), C 2 -C 4 alkenyl, C2-C 4 alkynyl, Ci-C 4 alkoxy, C 2 - C 4 alkanoyl, hydroxyCi-C 4 alkyl, (mono- and di-Ci-C 4 alkylamino)Co-C 4 alkyl, -Co-C 4 alkyl(C 3 - Cycycloalkyl), -0-Co-C 4 alkyl(C 3 -Cvcycloalkyl), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
• substituents independently chosen from halogen (and in particular F), hydroxyl, cyano, -COOH, Ci-C 4 alkyl (including in particular methyl), C 2
• the central core moiety is proline.
• the central core moiety is 4-fluoroproline.
• R 1 , R1' , R 2 ' , R 3 , and R 3' if present, are all hydrogen; and R 2 is fluoro.
• R 1 , R 1 , R 2 , and R 3 are all hydrogen; and R 2 is fluoro and R 3 is -Co-C 4 alkyl(C 3 -Cvcycloalkyl) or -0-Co-C 4 alkyl(C 3 -Cvcycloalkyl).
• 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.
• R 1 , R 1 , R 3 , and R 3 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.
• R 1 is hydrogen and R 2 is fluoro.
• R 1 and R 2 are joined to form a 3 membered ring.
• the disclosure includes compounds of Formula I in which the central pyrrolidine is vinyl substituted, for example:
• the compound of Formula I has the structure:
• the central pyrrolidine is modified by addition of a second heteroatom to a pyrrolidine ring, such as N, O, S, or Si, for example:
• Example compounds having the modifications disclosed above include:
• L is a bond or is chosen from the formulas:
• R 17 is hydrogen, Ci-C 6 alkyl, or -Co-C 4 alkyl(C3-Cycycloalkyl) and R 18 and R 18 are independently chosen from hydrogen, halogen, hydroxymethyl, and methyl; and m is 0, 1, 2, or
• B 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; -(Co-C 4 alkyl)(aryl); -(Co-C 4 alkyl)(heteroaryl); or -(Co- C 4 alkyl)(biphenyl) .
• R 33 is independently chosen from halogen, hydroxyl, -COOH, cyano, Ci-C 6 alkyl, C 2 -C 6 alkanoyl, Ci-C 6 alkoxy, -C 0 -C 4 alkylNR 9 R 10 , -S0 2 R 9 , C C 2 haloalkyl, and Ci-C 2 haloalkoxy;
• R 34 is independently chosen from nitro, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci- Cethioalkyl, -JC 3 -C 7 cycloalkyl, -B(OH) 2 , -JC(0)NR 9 R 23 ,-JOS0 2 OR 21 , -C(0)(CH 2 )i_ 4 S(0)R 21 , -0(CH 2 )i_ 4 S(0)NR 21 R 22 , -JOP(0)(OR 21 )(OR 22 ), -JP(0)(OR 21 )(OR 22 ), -JOP(0)(OR 21 )R 22 , -JP(0)(OR 21 )R 22 , -JOP(0)R 21 R 22 , -JP(0)R 21 R 22 , -JSP(0)(OR 21 )(OR 22 ), -JSP(0)(OR 21 )(R 22 ), -JSP(0)(OR 21 )(R 22 ), -JSP(0)(OR 21
• R may be unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH) 2 , -Si(CH 3 ) 3 , -COOH, -CONH 2 , -P(0)(OH) 2 , Ci-C 6 alkyl, -C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), Ci-C 6 alkoxy, -Co-C 2 alkyl(mono- and di-Ci-C 4 alkylamino), Ci-Cealkylester, Ci-C 4 alkylamino, Ci-C 4 hydroxylalkyl, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy;
• R 35 is independently chosen from naphthyl, naphthyloxy, indanyl, (4- to 7- membered heterocycloalkyl)Co-C 4 alkyl containing 1 or 2 heteroatoms chosen from N, O, and S, and bicyclic heterocycle containing 1 , 2, or 3 heteroatoms independently chosen 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 chosen from halogen, hydroxyl, nitro, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, Ci-C 6 alkoxy, (mono- and di-Ci- C 6 alkylamino)Co-C 4 alkyl, Ci-C 6 alkylester, -C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), -S0
• R 36 is independently chosen from tetrazolyl, (phenyl)C 0 -C 2 alkyl, (phenyl)Ci- C 2 alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing 1 , 2, or 3 heteroatoms independently chosen from N, O, B, and S, each of which R 36 is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, Ci-C 6 alkoxy, (mono- and di-Ci-C 6 alkylamino)Co-C 4 alkyl, Ci- C 6 alkylester, -C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), -S0 2 R 9 , -OSi(CH 3 ) 2 C(CH 3 ) 3 ,
• J is independently chosen at each occurrence from a covalent bond, Ci- C 4 alkylene, -OCi-C 4 alkylene, C 2 -C 4 alkenylene, and C 2 -C 4 alkynylene.
• -L-B- is , where
• R and R are independently chosen from hydrogen, halogen, hydroxyl, nitro, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, Ci-C 6 alkoxy, Ci-C 6 thioalkyl, -Co- C 4 alkyl(mono- and di-Ci-Cealkylamino), -Co-C 4 alkyl(C 3 -C 7 cycloalkyl), -Co-C 4 alkoxy(C 3 - C 7 cycloalkyl), Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, and Ci-C 2 haloalkylthio.
• R 18 and R 18 are independently chosen from hydrogen, halogen, hydroxymethyl, and methyl; and m is 0 or 1 ; and
• R , R , and R are independently chosen from hydrogen, halogen, hydroxyl, nitro, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, Ci-C 6 alkoxy, Ci-C 6 thioalkyl, (mono- and di-Ci-C 6 alkylamino)Co-C 4 alkyl, (C 3 -Cycycloalkyl)Co-C 4 alkyl, (aryl)Co-C 4 alkyl-, (heteroaryl)Co-
• C 3 -Cvcycloalkyl each of which R , R , and R other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, Ci-C 2 alkoxy, Ci-C 2 haloalkyl, (C 3 -C 7 cycloalkyl)Co-C 4 alkyl-, and Ci-C 2 haloalkoxy; and
• R 29 is hydrogen, Ci-C 2 alkyl, CiC 2 haloalkyl or -Si(CH 3 ) 2 C(CH 3 ) 3 .
• m is 0.
• the disclosure further includes compounds and salts of Formula I in which B is 2-fluoro-3-chlorophenyl.
• B is 2-fluoro-3-chlorophenyl.
• another carbocyclic, aryl, heterocyclic, or heteroaryl group such as 2-bromo-pyridin-6-yl, l-(2,2,2-trifluoroethyl)-lH- pyrazol-3-yl, 2,2-dichlorocyclopropylmethyl, or 2-fluoro-3-trimethylsilylphenyl is used.
• B is phenyl, pyridyl, or indanyl each of which is unsubstituted or substituted with one or more substituents independently chosen from hydrogen, halogen, hydroxyl, nitro, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, Ci-C 6 alkoxy, Ci- C 6 thioalkyl, (mono- and di-Ci-C 6 alkylamino)Co-C 4 alkyl, (C3-C 7 cycloalkyl)Co-C 4 alkyl, -C 0 - C 4 alkoxy(C3-C 7 cycloalkyl), (phenyl)Co-C 2 alkyl, (pyridyl)Co-C 2 alkyl; each of which substituents other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted with one or
• B is phenyl or pyridyl substituted with 1, 2, or 3 substituents chosen from chloro, bromo, hydroxyl, -SCF , Ci-C 2 alkyl, Ci-C 2 alkoxy, trifluoromethyl, phenyl and trifluoromethoxy each of which substituents other than chloro, bromo, hydroxyl, -SCF 3 , can be optionally substitued.
• B is a 2-fluoro-3-chlorophenyl or a 2-fluoro-3- trifluoromethoxyphenyl group.
• B is pyridyl, optionally substituted with halogen, Ci- C 2 alkoxy, and trifluoromethyl.
• B is phenyl, substituted with 1, 2, or 3 substituents independently selected from halogen, Ci-C 2 alkyl, Ci-C 2 alkoxy, trifluoromethyl, and optionally substituted phenyl.
• R 23 is independently chosen 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 chosen from N, O, and S, and (5- or 6- membered unsaturated or aromatic heterocycle)Co-C 4 alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S.
• B is selected from
• A is a group chosen from:
• R 4 is chosen from -CHO, -CONH 2 , C 2 -C 6 alkanoyl, hydrogen, -S0 2 NH 2 , -C(CH 2 ) 2 F, -CH(CF 3 )NH 2 , Ci-C 6 alkyl, -Co-C 4 alkyl(C 3 -C 7 cycloalkyl), -C(O)C 0 -C 2 alkyl(C 3 - C 7 cycloalkyl),
• each of which R 4 other than hydrogen, -CHO, and -CONH 2 is unsubstituted or substituted with one or more of amino, imino, halogen, hydroxyl, cyano, cyanoimino, Ci-C 2 alkyl, Ci-C 2 alkoxy, -Co-C 2 alkyl(mono- and di-Ci-C 4 alkylamino), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
• R 5 and R 6 are independently chosen from -CHO, -C(0)NH 2 , -C(0)NH(CH 3 ), C 2 - C 6 alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, -COOH, -S0 2 NH 2 , vinyl, Ci-C 6 alkyl (including methyl), C 2 -C 6 alkenyl, Ci-C 6 alkoxy, -Co-C 4 alkyl(C 3 -Cycycloalkyl), -C(O)C 0 - C 4 alkyl(C 3 -C 7 cycloalkyl), -P(0)(OR 9 ) 2 , -OC(0)R 9 , -C(0)OR 9 , -C(0)N(CH 2 CH 2 R 9 )(R 10 ), -NR 9 C(0)R 10 , phenyl, or 5- to 6-membered heteroaryl.
• R 5 and R 6 other than hydrogen, hydroxyl, cyano, and -COOH is unsubstituted or optionally substituted.
• R 5 and R 6 other than hydrogen, hydroxyl, cyano, and -COOH may be substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, imino, cyano, cyanoimino, Ci-C 2 alkyl, Ci-C 4 alkoxy, -C 0 - C 2 alkyl(mono- and di-Ci-C 4 alkylamino), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
• R 6 is hydrogen, halogen, hydroxyl, Ci-C 4 alkyl, -Co-C 4 alkyl(C 3 -C 7 cycloalkyl), or Ci-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, Ci-C 6 alkyl, or -C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl).
• R 8 and R 8 are independently chosen from hydrogen, halogen, hydroxyl, Ci- C 6 alkyl, -Co-C 4 alkyl(C 3 -C 7 cycloalkyl), Ci-C 6 alkoxy, and (Ci-C 4 alkylamino)Co-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 may include one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, Ci-C 6 alkoxy, -C 0 - C 4 alkyl(mono- and di-Ci-Cealkylamino), -Co-C 4 alkyl(C 3 -C 7 cycloalkyl), Ci-C 2 haloalkyl, and Ci- C 2 haloalkoxy.
• substituents independently chosen from halogen, hydroxyl, nitro, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, Ci-C 6 alkoxy, -C 0 - C 4 alkyl(mono- and di-Ci-Cealkylamino), -Co-C 4 alkyl(C 3 -C 7
• R 19 is hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, -S0 2 Ci-C 6 alkyl, (mono- and di-Ci-C 6 alkylamino)Ci-C 4 alkyl, -C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), -C 0 -C 4 alkyl(C 3 - C 7 heterocycloalkyl), -Co-C 4 alkyl(aryl), Co-C 4 alkyl(heteroaryl), and wherein R 19 other than hydrogen is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, -COOH, and -C(0)OCi-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 .
• R 11 , R 14 , and R 15 are independently chosen at each occurrence from hydrogen, halogen, hydroxyl, nitro, cyano, -0(PO)(OR 9 ) 2 , -(PO)(OR 9 ) 2 , C 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
• R 5 and R 6 are independently chosen from -CHO, -C(0)NH 2 , -C(0)NH(CH 3 ), C 2 -C 6 alkanoyl, and hydrogen.
• each R 5 and R 6 other than hydrogen, hydroxyl, cyano, and -COOH is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, imino, cyano, cyanoimino, Ci-C 2 alkyl, Ci-C 4 alkoxy, -Co- C 2 alkyl(mono- and di-Ci-C 4 alkylamino), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
• R 8 and R 8 are independently hydrogen or methyl.
• R 8 and R 8 are hydrogen.
• R 7 is hydrogen or methyl.
• R 7 is hydrogen
• this disclosure includes compounds and salts of Formula IA:
• this disclosure includes compounds and salts of Formula IB, IC, and I
• 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.
• R 13 is H
• B is phenyl
• R 1 , R 2 , R 2 , and R 3 are independently chosen from hydrogen, halogen, Ci- C 4 alkyl, Ci-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), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy;
• R 8 and R 8 are independently chosen from hydrogen, halogen, and methyl;
• R 5 is hydrogen, hydroxyl, cyano, -COOH, Ci-C 6 alkyl, Ci-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, Ci-C 2 haloalkyl, or C i -C 2 haloalkoxy ;
• R 6 is -C(0)CH 3 , -C(0)NH 2 , -C(0)CF 3 , -C(0)(cyclopropyl), or
• R 11 and R 14 are independently chosen from hydrogen, halogen, hydroxyl, amino, nitro, cyano, Ci-Cealkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, Ci-C 6 alkoxy, Ci-C 6 thioalkyl, -Co- C 4 alkyl(mono- and di-Ci-Cealkylamino), -Co-C 4 alkyl(C 3 -C 7 cycloalkyl), -OCo-C 4 alkyl(C 3 - C 7 cycloalkyl), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
• compositions comprising an effective amount of compound or pharmaceutically acceptable salt of Formula I, together with at least one pharmaceutically acceptable carrier.
• the pharmaceutical composition may contain a compound or salt of Formula I as the only active agent, or, in an alternative embodiment, Formula I and at least one additional active agent.
• 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 a compound of Formula I 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 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt.
• the pharmaceutical composition may also include a molar ratio of a compound of Formula I and an additional active agent.
• 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 another antiinflammatory agent.
• Compounds disclosed 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, intraveneous, intra-aortal, intracranial, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.
• the pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution.
• 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.
• Carriers include excipients and diluents and 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, flavorants, glidents, lubricants, preservatives, stabilizers, surfactants, 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.
• Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.
• compositions/combinations can be formulated for oral administration. These compositions can contain any amount of active compound for Formula I that achieves the desired result, for example between 0.1 and 99 weight % (wt.%) of a compound of Formula I and usually at least about 5 wt.% of a compound of Formula I. Some embodiments contain from about 25 wt.% to about 50 wt. % or from about 5 wt.% to about 75 wt.% of the compound of Formula I.
• the complement factor D inhibitors of the present invention can be administered, for example, either systemically or locally.
• Systemic administration includes, for example, oral, transdermal, subdermal, intraperitioneal, subcutaneous, transnasal, sublingual, or rectal.
• Local administration for ocular administration includes: topical, intravitreal, periocular, transscleral, retrobulbar, juxtascleral, sub-tenon, or via an intraocular device.
• the inhibitors may be delivered via a sustained delivery device implanted intravitreally or transsclerally, or by other known means of local ocular delivery.
• the compounds and pharmaceutical compositions disclosed herein are 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.
• the disorder is an inflammatory disorder, an immune disorder, an autoimmune disorder, or complement factor D related disorders in a host.
• the disorder is an ocular disorder.
• Complement mediated disorders that may be treated or prevented by the compounds and compositions of this disclosure include, but are not limited to, inflammatory effects of sepsis, systemic inflammatory response syndrome (SIRS), ischemia/ reperfusion injury (I/R injury), psoriasis, myasthenia gravis, system lupus erythematosus (SLE), paroxysmal nocturnal hemoglobinuria (PNH), hereditary angioedema, multiple sclerosis, trauma, burn injury, capillary leak syndrome, obesity, diabetes, Alzheimer's dementia, stroke, schizophrenia, epilepsy, age-related macular degeneration, glaucoma, diabetic retinopathy, asthma, allergy, acute respiratory distress syndrome (ARDS), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), cystic fibrosis, myocardial infarction, lupus nephritides, Crohn's disease, rheumatoid arthritis, at
• lung disease and disorders such as 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's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex- associated inflammation, uveitis (including Behcet's disease and other sub-types of uveitis), antiphospholipid syndrome, arthritis,
• COPD chronic ob
• 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.
• ophthalmic diseases including early or neovascular age-related macular degeneration and geographic atrophy
• autoimmune diseases including arthritis, rheumatoid arthritis
• respiratory diseases including cardiovascular diseases.
• 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.
• a method for the treatment of paroxysmal nocturnal hemoglobinuria includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
• a method for the treatment of age- related macular degeneration is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
• a method for the treatment of rheumatoid arthritis is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
• a method for the treatment of multiple sclerosis includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
• a method for the treatment of myasthenia gravis includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
• a method for the treatment of atypical hemolytic uremic syndrome (aHUS) is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
• a method for the treatment of C3 glomerulonephritis includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
• a method for the treatment of abdominal aortic aneurysm includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
• a method for the treatment of neuromyelitis optica (NMO) is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
• 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 a compound of Formula I of the invention.
• 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, by providing an effective amount of a compound or pharmaceutically acceptable salt of Formula I to patient with a factor D mediated inflammatory disorder.
• a compound or salt of Formula I may be provided as the only active agent or may be provided together with one or more additional active agents.
• a method for the treatment of a disorder associated with a dysfunction in the complement cascade includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
• a method of inhibiting activation of the alternative complement pathway in a subject includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
• a method of modulating factor D activity in a subject is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
• prevention means decreasing the likelihood of the appearance of symptoms in a patient administered the compound prophylactically as compared to the likelihood of the appearance of symptoms in patients not administered the compound or decreasing the severity of symptoms in a patient administered the compound prophylactically as compared to the severity of symptoms experienced by patients with the disorder or condition who were not administered the compound.
• an effective amount of a compound of Formula I is used to prevent or prophylaxis of a complement factor D related disorder.
• An effective amount of a pharmaceutical composition/ combination of the invention may be 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 disease; (b) cause a regression of an inflammatory, immune, including an autoimmune, disorder or complement factor D related disease; or (c) cause a cure of an inflammatory, immune, including an autoimmune, disorder or complement factor D related disease.
• An effective amount of a compound or pharmaceutical composition described herein will also provide a sufficient amount of the active agent when administered to a patient to provide a clinical benefit. Such an amount may be ascertained experimentally, for example by assaying blood concentration of the agent, or theoretically, by calculating bioavailability.
• a compound or salt of Formula I 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.
• a compound or salt of Formula I may be provided in combination with a complement C5 inhibitor or C5 convertase inhibitor.
• a compound or salt of Formula I may be provided in combination with eculizumab.
• a compound or salt of Formula I may be provided in combination with additional inhibitors of factor D.
• a compound or salt of Formula I may be provided together with a compound that inhibits an enzyme that metabolizes protease inhibitors. In one embodiment, a compound or salt of Formula I may be provided together with ritonavir.
• a compound or salt of Formula I may be provided together with a protease inhibitor, a soluble complement regulator, a therapeutic antibody (monoclonal or polyclonal), complement component inhibitors, receptor agonists, or siRNAs.
• Nonlimiting examples of active agents in these categories are:
• Protease inhibitors plasma-derived Cl-INH concentrates, for example Cetor® (Sanquin), Berinert-P® (CSL Behring, Lev Pharma), and Cinryze®; and recombinant human CI -inhibitors, for example Rhucin®;
• Soluble complement regulators Soluble complement receptor 1 (TP 10) (Avant
• Immunotherapeutics sCRl-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 include Compstatin/POT-4 (Potentia Pharmaceuticals); ARC 1905 (Archemix);
• Receptor agonists PMX-53 (Peptech Ltd.); JPE-137 (Jerini); JSM-7717 (Jerini); [0316] Others: Recombinant human MBL (rhMBL; Enzon Pharmaceuticals).
• 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 a composition comprising a compound of the current invention.
• AMD age-related macular degeneration
• the compositions of the present invention are administered in combination with an anti-VEGF agent.
• Nonlimiting 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.
• a compound of Formula I can be combined with a second agent in order to treat a disorder of the eye.
• Examples of types of therapeutic agents that can be used in combination for ocular applications include anti-inflammatory drugs, antimicrobial agents, anti-angiogenesis agents, immunosuppressants, antibodies, steroids, ocular antihypertensive drugs and combinations thereof.
• therapeutic 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, itrac
• 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' endothelial dystrophy, Sjogren'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-prolife
• a compound of Formula I, or a combination of Formula I and another active agent can be administered into an eye compartment of via injection into the vitreous chamber, subretinal space, subchoroidal space, the episclera, the conjunctiva, the sclera, the anterior chamber, and the cornea and compartments therein (e.g., subepithelial, intrastromal, endothelial).
• a compound of Formula I, or a combination of Formula I and another active agent can be administered into an eye compartment via binding to a mucosal penetrating particle to treat a condition located in the vitreous chamber, subretinal space, subchoroidal space, the episclera, the conjunctiva, the sclera or the anterior chamber, and the cornea and compartments therein (e.g., subepithelial, intrastromal, endothelial).
• Mucosal penetrating particles are known in the art, and are described in, for example, PCT published application WO 2013166436 to Kala Pharmaceuticals, incorporated in its entirety herein.
• a composition comprising compound of Formula I suitable for topical administration to an eye.
• the pharmaceutical composition comprises a plurality of coated particles, comprising a core particle comprising a compound of Formula I, wherein Formula I constitutes at least about 80 wt% of the core particle, and a coating comprising one or more surface-altering agents, wherein the one or more surface-altering agents comprise at least one of a poloxamer, a poly(vinyl alcohol), or a polysorbate.
• the one or more surface-altering agents is present on the outer surface of the core particle at a density of at least 0.01 molecules/nm.
• the one or more surface-altering agents is present in the pharmaceutical composition in an amount of between about 0.001% to about 5% by weight.
• the plurality of coated particles have an average smallest cross-sectional dimension of less than about 1 micron.
• the pharmaceutical composition also includes one or more ophthalmically acceptable carriers, additives, and/or diluents.
• particles suitable for use with the presently disclosed methods can exist in a variety of shapes, including, but not limited to, spheroids, rods, disks, pyramids, cubes, cylinders, nanohelixes, nanosprings, nanorings, rod- shaped particles, arrow-shaped particles, teardrop-shaped particles, tetrapod- shaped particles, prism-shaped particles, and a plurality of other geometric and non-geometric shapes.
• the presently disclosed particles have a spherical shape.
• 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 a composition comprising a compound of the current invention. 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 a composition comprising a compound of the current invention in combination or alternation with additional inhibitors of the complement system or another active compound with a different biological mechanism of action.
• PNH paroxysmal nocturnal hemoglobinuria
• 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 a composition comprising a compound of the current invention in combination or alternation with eculizumab.
• PNH paroxysmal nocturnal hemoglobinuria
• 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 a compound of the current invention. 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 a compound of the current invention in combination or alternation with an additional inhibitor of the complement system. 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 a composition comprising a compound of the current invention in combination or alternation with methotrexate.
• a compound of Formula I is administered in combination or alternation with at least one anti-rhuematoid arthritis drug 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 diclofenac
• the present invention provides a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of a composition comprising a compound of the current invention. 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 a composition comprising a compound of the current invention in combination or alternation with additional inhibitors of the complement system. 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 a composition comprising a compound of the current invention in combination or alternation with a corticosteroid. Examples of corticosteroids include, but are not limited to, prednisone, dexamethasone, solumedrol, and methylprednisolone.
• a compound of Formula I is combined with at least one anti- multiple sclerosis drug selected from: Aubagio (teriflunomide), Avonex (interferon beta- la), Betaseron (interferon beta- lb), Copaxone (glatiramer acetate), Extavia (interferon beta- lb), Gilenya (fingolimod), Lemtrada (alemtuzumab), Novantrone (mitoxantrone), Plegridy (peginterferon beta- la), Rebif (interferon beta- la), Tecfidera (dimethyl fumarate), Tysabri (natalizumab), Solu-Medrol (methylprednisolone), High-dose oral Deltasone (prednisone), H.P. Acthar Gel (ACTH), and combinations thereof.
• Aubagio teriflunomide
• Avonex interferon beta- la
• Betaseron interferon beta- lb
• Copaxone g
• a compound or salt of Formula I may be provided in combination or alternation with an immunosuppressive agent or an anti-inflammatory agent.
• a compound described herein can be administered in combination or alternation with at least one immunosuppressive agent.
• the immunosuppressive agent as nonlimiting 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 SIP 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, natal
• 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,
• a compound of Formula I 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.
• NSAIDs non-steroidal anti-inflammatory drugs
• a compound of the present invention can be prepared, for example, from a central core.
• the central core is coupled to an amine to generate an amide of Structure 2 (wherein L-B includes a C(0)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. removal of
• central core Structure 5 is reacted with a heterocyclic or heteroaryl compound to generate a compound of Structure 6.
• Structure 6 is deprotected to generate a carboxylic acid, Structure 7.
• Structure 7 is coupled to an amine to generate a compound of Formula I. This chemistry is illustrated in Route 2.
• Route 2 [0335] 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.
• a heteroaryl compound of Structure 10 is coupled to an activated ester, Structure 11, to generate Structure 12.
• the ester is hydro lyzed to form acid Structure 13.
• Structure 13 is coupled to Structure 3 from Route 1 to generate Structure 14.
• Structure 14 is treated with a base such as, but not limited to, lithium hydroxide to generate Structure 15. This chemistry is illustrated in Route 4.
• Structure 15 is treated with diphenylphosphoryl azide (DPPA) to generate the isocyanate, Structure 16.
• Structure 16 is then treated with an amine or alcohol to generate ureas and carbamates compounds of Formula I, wherein the R 12 substituent is NR 9 C(0)NR 9 R 10 , NR 9 C(O)NR 10 R 23 , NR 9 C(0)R 24 R 25 , NR 9 C(0)OR 10 or NR 9 C(0)OR 23 .
• R 9 is hydrogen.
• Structure 15 can be coupled to amines to generate amides of Formula I, wherein the R 12 substituent is, C(0)NR 24 R 25 , C(0)NR 9 R 37 , or C(0)NR 21 S0 2 R 22 .
• R 9 is hydrogen.
• the chemistry is illustrated in Route 5.
• a heteroaryl compound of Structure 17 is coupled to an activated ester to generate Structure 18.
• the ester is hydro lyzed to form acid Structure 19.
• Structure 19 is coupled to Structure 3 from Route 1 to generate Structure 20.
• Structure 20 is treated with a base such as, but not limited to, lithium hydroxide to generate Structure 21. This chemistry is illustrated in Route 6.
• Structure 21 from Route 6 is treated with, for example, diphenylphosphoryl azide (DPP A) to generate an isocyanate, Structure 22.
• Structure 22 is then treated with an amine or alcohol to generate urea and carbamate compounds within Formula I, wherein the R 13 substituent is NR 9 C(0)NR 9 R 10 , NR 9 C(O)NR 10 R 23 , NR 9 C(0)R 24 R 25 , NR 9 C(0)OR 10 and NR 9 C(0)OR 23 .
• R 9 is hydrogen.
• Structure 21 can be coupled to amines to generate amides within Formula I, wherein the R 13 substituent is
• a heteroaryl or aryl moiety is coupled to a central core to generate 8-2.
• the protected acid, 8-2 is deblocked to form the carboxylic acid, 8-3.
• the carboxylic acid is coupled to form an amide bond (L-B) and 8-4.
• the heteroaryl or aryl moiety, A' can then be further derivitized to add substituents at the X 11 , X 12 , X 13 and X 14 positions to generate compounds within Formula I. This chemistry is illustrated in Route 8.
• Structure 9-1 is coupled to an acid, Structure 9-2, to generate Structure 9-3.
• the carboxylic acid, Structure 9-3 is deblocked to generate carboxylic acid, Structure 9-4.
• Carboxylic acid Structure 9-4 is coupled to an amine to form an amide bond (L-B) and compounds within Formula I. This chemistry is illustrated in Rout
• a heteroaryl compound of Structure 10-1 is treated with a carboxylic acid to generate Structure 10-2.
• the heteroaryl Structure 10-2 can be treated with an acylating agent to generate Structure 10-3.
• the nitrile can be treated with an oxime to generate an amide at the R 6 position.
• Structure 10-3 is treated with an activated ester to generate Structure 10-4.
• the leaving group, LG is a halide.
• Structure 10- 4 is treated with a base to generate the acid, Structure 10-5.
• Structure 10-5 can be coupled to Structure 3 from Route 1 to generate compounds within Formula I. This chemistry is illustrated in Route 10.
• a heteroaryl compound of Structure 11-1 is treated with a carboxylic acid to generate Structure 11-2.
• the heteroaryl Structure 11-2 can be treated with an acylating agent to generate Structure 11-3.
• the nitrile can be treated with an oxime to generate an amide at the R 6 position.
• Structure 11-3 is treated with an activated ester to generate Structure 11-4.
• the leaving group, LG is a halide.
• Structure 11- 4 is treated with a base to generate the acid, Structure 11-5.
• Structure 11-5 is coupled to Structure 3 from Route 1 to generate compounds within Formula I. The chemistry is illustrated in Route 11.
• a heteroaryl compound of Structure 12-1 is treated with a carboxylic acid to generate Structure 12-2.
• the heteroaryl Structure 12-2 can be treated with an acylating agent to generate Structure 12-3.
• the nitrile can be treated with an oxime to generate an amide at the R 6 position.
• Structure 12-3 is treated with an activated ester to generate Structure 12-4.
• the leaving group, LG is a halide.
• Structure 12- 4 is treated with a base to generate the acid, Structure 12-5.
• Structure 12-5 can be coupled to Structure 3 from Route 1 to generate compounds within Formula I. This chemistry is illustrated in Route 12.
• a heteroaryl compound of Structure 13-1 is treated with a carboxylic acid to generate Structure 13-2.
• the heteroaryl Structure 13-2 can be treated with an acylating agent to generate Structure 13-3.
• the nitrile can be treated with an oxime to generate an amide at the R 6 position.
• Structure 13-3 is treated with an activated ester to generate Structure 13-4.
• the leaving group, LG is a halide.
• Structure 13- 4 is treated with a base to generate the acid, Structure 13-5.
• Structure 13-5 can be coupled to Structure 3 from Route 1 to generate compounds within Formula I. The chemistry is illustrated in Route 13.
• Structure 14-1 is coupled to an amine to generate an amide bond (L-B), and Structure 14-2.
• Structure 14-2 is coupled to an amine to generate compounds within Formula I. This chemistry is illustrated in Route 14.
• Z A is halogen
• deuterated L-proline synthons are disclosed.
• Deuterated s nthons 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.
• Compound F can be used to generate Structure K.
• Structure G can be treated with DAST to generate Structure H.
• Structure F can be used to generate Structure K.
• 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.
• 5-azaspiro[2.4]heptane-4,5-dicarboxylic acid, 5-(l,l-dimethylethyl) ester, (45)-, CAS 209269-08-9 can be prepared as described in Tandon, M. et al. Bioorg. Med. Chem. Lett. 1998, 8, 1139-1144.
• 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.
• the amine is (3-chloro-2-fluorophenyl) methanamine.
• the organic solvent is DMF.
• the base is diisopropylethylamine.
• the coupling reagent is HATU.
• the protecting group is removed.
• the starting material is reacted with an acid in the presence of an organic solvent.
• the acid is 4N hydrochloric acid.
• the organic solvent is dioxane.
• 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.
• the amine is (3-chloro-2-fluorophenyl) methanamine.
• the organic solvent is DMF.
• the base is diisopropylethylamine.
• the coupling reagent is HATU.
• the protecting group is removed.
• the starting material is reacted with an acid in the presence of an organic solvent.
• the acid is 4N hydrochloric acid.
• the organic solvent is dioxane.
• 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.
• the amine is (3-chloro-2- fluorophenyl) methanamine.
• the organic solvent is DMF.
• the base is diisopropylethylamine.
• the coupling reagent is HATU.
• Step 3 the protecting group is removed.
• the starting material is reacted with an acid in the presence of an organic solvent.
• the acid is 4N hydrochloric acid.
• the organic solvent is dioxane.
• 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.
• the amine is (3-chloro-2-fiuorophenyl) methanamine.
• the organic solvent is DMF.
• the base is diisopropylethylamine.
• the coupling reagent is HATU.
• the Boc protecting group is removed.
• the starting material is reacted with an acid in the presence of an organic solvent.
• the acid is 4N hydrochloric acid.
• the organic solvent is dioxane.
• Additional starting materials that can readily be converted to Central-L-B- Synthons include, but are not limited to: (S)-l-(tert-butoxycarbonyl)-2,3-dihydro-lH-pyrrole-2- carboxylic acid, CAS 90104-21-5, available from Ark Pharm; cyclopent-l-ene-l,2-dicarboxylic acid, CAS 3128-15-2, purchased from Ark Pharm; imidazole, lH-imidazole-l,2-dicarboxylic acid, l-(l,l-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, OH
• the compounds (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-l,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-l,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.
• a heteroaryl compound of Structure 1 is acylated to generate a compound of Structure 2.
• Structure 2 is coupled to an activated ester of Structure 3 to generate Structure 4.
• the ester is hydro lyzed to form acid Structure 5. This chemistry is ill trated in Scheme 4a.
• a heteroaryl compound, Structure 2-1 is treated with a halogen to generate Structure 2-2.
• the halogen is iodine.
• Structure 2-2 is treated with an activated ester to generate Structure 2-3.
• the halide is treated with zinc cyanide to generate nitrile, Structure 2-4.
• the nitrile, Structure 2-4 is treated with an oxime to generate the amide Structure 2-5.
• the ester is treated with an acid to generate acid, Structure 2- 6. This chemistry is illustrated in Scheme 4b.
• Structure 5 from Example 4 Scheme 4a, is coupled to Structure 3 from Route 1 to generate Structure 6.
• Structure 6 is treated with a base such as, but not limited to, lithium hydroxide to generate Structure 7. This chemistry is illustrated in Scheme 5a.
• Structure 2-6 from Example 4b is coupled to a central core- L-B to generate Structure 2-7.
• Structure 2-7 is treated with a base to generate a carboxylic acid, Structure 2-8.
• the base is lithium hydroxide. This chemistry is illustrated in Scheme 5b. Structure 2-6
• Structure 1 is treated with, for example, diphenylphosphoryl azide (DPP A) to generate an isocyanate, Structure 2.
• Structure 2 is then treated with an amine or alcohol to generate urea and carbamate compounds within Formula I, wherein the R 13 substituent is NR 9 C(0)NR 9 R 10 , NR 9 C(O)NR 10 R 23 , NR 9 C(0)R 24 R 25 , NR 9 C(0)OR 10 and NR 9 C(0)OR 23 .
• R 9 is hydrogen.
• Structure 1 can be coupled to amines to generate amides within Formula I, wherein the R 13 substituent is C(0)NR 24 R 25 , C(0)NR 9 R 37 , or C(0)NR 21 S0 2 R 22 .
• R 9 is hydrogen.
• the chemistry is illustrated in Scheme 6a.
• reaction mixture was diluted with 1M citric acid solution (200ml + NaCl solid 20gm) and extracted with DCM (150 mL x 2), the organic layer was then washed with an aqueous solution of NaHC0 3 (100 ml) and washed with water (100 ml), brine (100 ml) and dried over Na 2 S0 4 and concentrated under reduced pressure. The remaining residue was purified by column chromatography (eluted with DCM/EtOAc) to give (2S,4R)-tert-butyl 2-((3-chloro-2-fhiorobenzyl)carbamoyl)-4- fluoropyrrolidine- 1 -carboxylate.
• 6-Benzyloxyindole was acetylated using reported procedure (Eur. J. Med Chem., (2011), 46, 756) and alkylated following the procedure describe for compound B.
• the benzyl group was removed by hydrogenation over palladium on charcoal and the t-butyl group removed again as described for compound B.
• reaction mixture was then stirred for 18 h at RT, diluted with 1 M citric acid solution (100 mL, containing 10 g NaCl), and extracted with DCM (50 mL x 2).
• the organic layer was washed with an aqueous solution of NaHC0 3 (40 mL), washed with water (40 mL), washed with brine (40 mL), dried over Na 2 S0 4 , and concentrated under reduced pressure.
• reaction mixture was concentrated under reduced pressure and the remaining residue was purified by flash column chromatography (silica gel eluted with DCM/CH 3 OH) to give product cyclopropyl (3 -acetyl- 1 -(2-((25,4R)-2-((3 -chloro- 2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-l-yl)-2-oxoethyl)-lH-indol-5-yl)carbamate (187).
• Methyl 3-acetyl-lH-indole-6-carboxylate was prepared according to the procedure published by MacKay et al. (MacKay, J. A.; Bishop, R.; Rawal, V. H. Org. Lett. 2005, 7, 3421-3424.)
• reaction mixture was diluted with 1M citric acid solution (200 mL + NaCl solid 20 g) and extracted with DCM (150 mL x 2). The organic layer was then washed with an aqueous NaHC0 3 (100 mL), water (100 mL), brine (100 mL), dried over Na 2 S0 4 and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (eluent: DCM/EtOAc) to give (2S,4R)-tert-butyl 2-((3-chloro-2- fluorobenzyl)carbamoyl)-4-fluoropyrrolidine- 1 -carboxylate, compound N.
• reaction mixture was diluted with 1M citric acid solution (200 mL + NaCl solid 20 g) and extracted with DCM (150 mL x 2), the organic layer was then washed with an aqueous solution of NaHC0 3 (100 mL), water (100 mL), brine (100 mL), dried over Na 2 S0 4 and concentrated under reduced pressure.
• reaction mixture was added to water (20 mL) and extracted with DCM (2 ⁇ 25 mL). The organic layer was washed successively with an aqueous solution of NaHC0 3 (20 mL), water (20 mL), and brine (20 mL), then dried over Na 2 S0 4 and concentrated under reduced pressure.
• reaction mixture was diluted with 1M citric acid solution (100 mL + NaCl solid 10 g) and extracted with DCM (50 mL x 2), the organic layer was then washed with an aqueous solution of NaHC0 3 (40 mL) and washed with water (40 mL), brine (40 mL) and dried over Na 2 S0 4 and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography over silica gel (eluent: DCM/CH 3 OH) to give compound AB.
• Compound AM was prepared from 2-(3-acetyl-5-(methoxycarbonyl)-lH-indol-l- yl)acetic acid (D, 275 mg) and (lR,3S,5R)-N-(3-chloro-2-fluorobenzyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride (T, 305 mg) to give compound AL and then hydrolyzed following procedures described in Scheme 10.
• Compound AO was prepared from 2-(3-acetyl-5-(methoxycarbonyl)-lH-indol-l- yl)acetic acid (D, 275 mg) and (2S,4R)-N-(2 * -chloro-2-fluoro-[l,r-biphenyl]-3-yl)-4- fluoropyrrolidine-2-carboxamide hydrochloride (L, 373 mg) ) to give compound AN and then hydrolyzed following procedures described in Scheme 10.
• Compound AQ was prepared from 2-(3-acetyl-6-(methoxycarbonyl)-lH-indol-l- yl)acetic acid (E, 275 mg) and (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2- carboxamide hydrochloride (O, 311 mg) to give compound AP and then hydrolyzed following procedures described in Scheme 10.
• Compound AS was prepared from 2-(3-carbamoyl-5-(methoxycarbonyl)-lH- indazol-l-yl)acetic acid (F, 277 mg) and (2S,4R)-N-(2'-chloro-2-fluoro-[l,l'-biphenyl]-3-yl)-4- fluoropyrrolidine-2-carboxamide hydrochloride (L, 373 mg) to give compound AR and then hydrolyzed following procedures described in Scheme 10.
• Compound AU was prepared from 2-(3-carbamoyl-5-(methoxycarbonyl)-lH- indazol-l-yl)acetic acid (F, 277 mg) and (lR,3S,5R)-N-(2 * -chloro-2-fiuoro-[l,r-biphenyl]-3-yl)-
• Compound AW was prepared from 2-(3-Carbamoyl-5-(methoxycarbonyl)-lH- indazol-l-yl)acetic acid (F, 277 mg) and (2S,4R)-N-(3-(3-chloropyridin-2-yl)-2-fluorophenyl)-4- fluoropyrrolidine-2-carboxamide hydrochloride (X, 374 mg) to give compound AT and then hydrolyzed following procedures described in Scheme 10.
• Compound AY was prepared from 2-(3-Carbamoyl-5-(methoxycarbonyl)-lH- indazol-l-yl)acetic acid (F, 277 mg) and (2S,4R)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-
• N-(3-acetyl-lH-indol-5-yl)-3,3-difluorocyclopentanecarboxamide (BE, 8 mg), tert-butyl 2-bromoacetate(5.6 mg) and K 2 CO 3 (4.1 mg) in ACN (10 mL) was stirred at 60 °C for 5h. Solvent was removed and residue purified by chromatography over silica gel to afford tert- butyl 2-(3-acetyl-5-(3,3-difluorocyclopentanecarboxamido)-lH-indol-l-yl)acetate (BF).
• Table 1 shows illustrative compounds of Formula I with characaterizing data.
• the assay of Example 14 was used to determine the ICso'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.
• 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's reagent) are added to final concentrations of 100 ⁇ each.
• the increase in color is recorded at OD405 nm in a microplate in kinetic mode over 30 minutes with 30 second time points in a spectra fluorimeter.
• IC50 values are calculated by non- linear regression from the percentage of inhibition of complement factor D activity as a function of test compound concentration.
• the hemolysis assay was previously described by G. Ruiz-Gomez, et al, J. Med. Chem. (2009) 52: 6042-6052.
• red blood cells RBC
• rabbit erythrocytes purchased from Complement Technologies
• GVB Buffer 0.1 % gelatin, 5 mM Veronal, 145 mM NaCl, 0.025 % NaN 3 , pH 7.3
• Cells are used at a concentration of 1 x 10 8 cells/mL.
• the optimum concentration of Normal Human Serum (NHS) needed to achieve 100% lysis of rabbit erythrocytes is determined by titration.
• NHS (Complement Technologies) is incubated with inhibitor for 15 min at 37 °C, rabbit erythrocytes in buffer were added and incubated for an additional 30 min at 37 °C.
• Positive control (100% lysis) consists of serum and RBC and negative control (0% lysis) of Mg-EGTA buffer and RBC only. Samples are centrifuged at 2000g for 5 min, and supernatants collected. Optical density of the supernatant is monitored at 405 nm using a UV/visible spectrophotometer. Percentage lysis in each sample is calculated relative to positive control (100% lysis).
• variables e.g, A, B, L, X 1 , X 2 , Q 1 , Q 2 , and Q 3 carry the following values.
• Q 1 is N(R J ) or QRV).
• Q 2 is C(R 2 R 2' ), C(R 2 R 2' )-C(R 2 R 2' ), or C(R 2 R 2' )0.
• Q 3 is N(R 3 ), S, or C(R 3 R 3' ).
• R , R , R , R , and R are independently chosen at each occurence from (c) and (d):
• any one of the following rings (e), (f), (g), (h), (i), or j) may be present:
• 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 chosen from N, O, or S;
• R 2 and R 2 may be taken together to form a 3- to 6-membered carbocyclic spiro ring
• R 2 and R 2 ' may be taken together to form a 3- to 6-membered heterocyclic spiro ring
• each of which spiro rings (e), (f), and (g) is unsubstituted or substituted with one or more halogen or methyl substituents;
• R 1 and R 2 may be taken together to form a 3-membered carbocyclic ring; [0476] (i) R 1 and R 2 may be taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently chosen from N, O, and S.
• R 2 and R 3 if bound to adjacent carbon atoms, may be taken together to form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring; each of which ring (g), (h), and (i) may be unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, cyano, -COOH, Ci-C 4 alkyl, C 2 -C 4 alkenyl, Ci-C 4 alkoxy, C 2 - C 4 alkanoyl, hydroxyCi-C 4 alkyl, (mono- and di-Ci-C 4 alkylamino)Co-C 4 alkyl, -Co-C 4 alkyl(C 3 - Cycycloalkyl), -0-Co-C 4 alkyl(C 3 -Cvcycloalkyl), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy;
• A is a heterocyclic group chosen from (k) and (1) where (k) is
• X 4 is B(OH) and Y is CHR 9 ; or X 4 is CHR 9 and Y is B(OH).
• R 4 is (m) or (n):
• R 5 and R 6 are independently chosen from (o) and (p):
• Each R 5 and R 6 other than hydrogen, hydroxyl, cyano, and -COOH is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, imino, cyano, cyanoimino, Ci-C 2 alkyl, Ci-C 4 alkoxy, -Co-C 2 alkyl(mono- and di-Ci-C 4 alkylamino), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
• R 6 is hydrogen, halogen, hydroxyl, Ci-C 4 alkyl, or Ci-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 C 6 alkyl, or -C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl.
• R 8 and R 8 ' are independently chosen from hydrogen, halogen, hydroxyl, Ci- C 6 alkyl, Ci-C 6 alkoxy, and (Ci-C 4 alkylamino)Co-C 2 alkyl, or R 8 and R 8 are taken together to form an oxo group.
• R 16 is 0 or 1 or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, Ci-C 6 alkoxy, -Co-C 4 alkyl(mono- and di- Ci-Cealkylamino), -Co-C 4 alkyl(C 3 -Cycycloalkyl), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
• R 19 is hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, -S0 2 Ci-C 6 alkyl, (mono- and di-Ci-C 6 alkylamino)Ci-C 4 alkyl, -Co-C 4 alkyl(C 3 -Cycycloalkyl), each of which R 19 other than hydrogen is substituted with 0 or 1 or more substituents independently chosen from halogen, hydroxyl, amino, -COOH, and -C(0)OCi-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 .
• X 15 is N or CR 15 .
• R 11 , R 14 , and R 15 are independently chosen at each occurrence from hydrogen, halogen, hydroxyl, nitro, cyano, -0(PO)(OR 9 ) 2 , -(PO)(OR 9 ) 2 , C C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkanoyl, Ci-C 6 alkoxy, Ci-C 6 thioalkyl, -C 0 -C 4 alkyl(mono- and di-Ci-C 6 alkylamino), -C 0 - C 4 alkyl(C 3 -Cycycloalkyl), -Co-C 4 alkoxy(C 3 -Cycycloalkyl), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
• R 12 and R 13 are independently chosen from (q), (r), and (s):
• J is independently chosen at each occurrence from a covalent bond, Ci- C 4 alkylene, -OCi-C 4 alkylene, C 2 -C 4 alkenylene, and C 2 -C 4 alkynylene.
• R 21 and R 22 are independently chosen at each occurrence from hydrogen, hydroxyl, cyano, amino, Ci-C 6 alkyl, Ci-C 6 alkyl, Ci-C 6 alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (phenyl)C 0 -C 4 alkyl, -Ci-C 4 alkylOC(0)OCi-C 6 alkyl, -Ci-C 4 alkylOC(0)Ci-C 6 alkyl, -C C 4 alkylC(0)OCi-C 6 alkyl, (4- to 7-membered heterocycloalkyl)Co-C 4 alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6- membered unsaturated or aromatic heterocycle)Co-C 4 alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S.
• R 23 is independently chosen at each occurrence from (C 3 -C 7 cycloalkyl)Co- C 4 alkyl, (phenyl)Co-C 4 alkyl, (4- to 7-membered heterocycloalkyl)Co-C 4 alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6- membered unsaturated or aromatic heterocycle)Co-C 4 alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S.
• 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.
• each of which (s) may be unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH) 2 , -Si(CH 3 ) 3 , -COOH, -CONH2, -P(0)(OH) 2 , Ci-C 6 alkyl, Ci-C 6 alkoxy, -C 0 -C 2 alkyl(mono- and di- Ci-C 4 alkylamino), Ci-Cealkylester, Ci-C 4 alkylamino, Ci-C 4 hydroxylalkyl, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
• substituents independently chosen from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH) 2 , -Si(CH 3 ) 3 , -COOH, -CONH2, -P(0)(
• L is either (t), (u), or (v):
• Ci-C 6 alkyl and R 18 and R 18 are independently chosen from hydrogen, halogen, and methyl; and m is 0, 1, 2, or 3; and
• B is a monocyclic or bicyclic carbocyclic or carbocyclic-oxy group or 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, or B is a C 2 - C 6 alkenyl or C 2 -C 6 alkynyl group.
• Either X 2 is nitrogen or at least one of (d), (e), (g), (i), (1), (n), (p), (s), (v), (x), and (y) is present.
• Pharmaceutical composition comprising a compound or salt of Formula I together with a pharmaceutically acceptable carrier are also disclosed.
• Forma I encompasses all compounds that satisfy Formula I, including any enantiomers, racemates and stereoisomers, as well as all pharmaceutically acceptable salts of such compounds.
• “Formula I” includes all subgeneric groups of Formula I, such as Formula IA and Formula IB and also includes pharmaceutically acceptable salts of a compound of Formula I, unless clearly contraindicated by the context in which this phrase is used.
• Compounds of Formula I include all compounds of Formula I having isotopic substitutions at any position.
• Isotopes include those atoms having the same atomic number but different mass numbers.
• isotopes of hydrogen include tritium and deuterium and isotopes of carbon include U C, 13 C, and 14 C. While the compounds of Formula I require a moderate or high level of deuteration (substitution of a hydrogen with deuterium) at identified positions, Formula I includes embodiments in which other positions are isotopically enriched.
• An "active agent” means a compound (including a compound disclosed herein), element, or mixture that when administered to a patient, alone or in combination with another compound, element, or mixture, confers, directly or indirectly, a physiological effect on the patient.
• the indirect physiological effect may occur via a metabolite or other indirect mechanism.
• a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
• Alkyl is a branched or straight chain saturated aliphatic hydrocarbon group, having the specified number of carbon atoms, generally from 1 to about 12 carbon atoms.
• Ci-C 6 alkyl indicates an alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms.
• Other embodiments include alkyl groups having from 1 to 8 carbon atoms, 1 to 4 carbon atoms or 1 or 2 carbon atoms, e.g. Ci-Cgalkyl, Ci-C 4 alkyl, and Ci-C 2 alkyl.
• Co-C n alkyl When Co-C n alkyl is used herein in conjunction with another group, for example, (C 3 -Cycycloalkyl)Co-C 4 alkyl, or -Co-C 4 alkyl(C 3 -Cycycloalkyl), the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (Coalkyl), or attached by an alkyl chain having the specified number of carbon atoms, in this case 1, 2, 3, or 4 carbon atoms. Alkyls can also be attached via other groups such as heteroatoms as in -0-Co-C 4 alkyl(C 3 -Cycycloalkyl).
• alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t-butyl, n-pentyl, and sec-pentyl.
• alkenyl is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at any stable point along the chain, having the specified number of carbon atoms. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.
• Alkynyl is a branched or straight chain aliphatic hydrocarbon group having one or more double carbon-carbon triple bonds that may occur at any stable point along the chain, having the specified number of carbon atoms.
• Alkylene is a bivalent saturated hydrocarbon. Alkylenes include groups having 1 to 8 carbon atoms, 1 to 6 carbon atoms, or the indicated number of carbon atoms, for example Ci-C 4 alkylene.
• Alkenylene is a bivalent hydrocarbon having at least one carbon-carbon double bond. Alkenylenes include groups having 2 to 8 carbon atoms, 2 to 6 carbon atoms, or the 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 include groups having 2 to 8 carbon atoms, 2 to 6 carbon atoms, or the indicated number of carbon atoms, for example C 2 -C 4 alkenylene.
• Alkoxy is an alkyl group as defined above with the indicated number of carbon atoms covalently bound to the group it substitutes by an oxygen bridge (-0-).
• 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.
• an "Alkylthio" or a "thioalkyl” group is an alkyl group as defined above with the indicated number of carbon atoms covalently bound to the group it substitutes by a sulfur bridge (-S-).
• Alkenyloxy is an alkenyl group as defined above with the indicated number of carbon atoms covalently bound to the group it substitutes by an oxygen bridge (-0-).
• Alkylester is an alkyl group as defined herein covalently bound to the group it substitutes by an ester linkage.
• Carbocyclic group is a saturated, unsaturated, or partially unsaturated (e.g. 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.
• Carbocyclic ring is a saturated, unsaturated, or partially unsaturated (e.g. aromatic) ring containing all carbon ring atoms.
• a carbocyclic ring typically contains 1 ring of 3 to 7 carbon atoms or a "carbocyclic group” may contain 1 carbocyclic ring or 2 fused carbocyclic rings each containing 3 to 7 carbon atoms. Examples of carbocyclic rings include phenyl, cyclohexenyl, cyclohexyl, and cyclopropyl rings.
• 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, -0-, linker.
• Cycloalkyl is a saturated hydrocarbon ring group, having the specified number of carbon atoms.
• Monocyclic cycloalkyl groups typically have from 3 to about 8 carbon ring atoms or from 3 to 7 (3, 4, 5, 6, or 7) carbon ring atoms.
• Cycloalkyl substituents may be pendant from a substituted nitrogen or carbon atom, or a substituted carbon atom that may have two substituents may have a cycloalkyl group, which is attached as a spiro group.
• Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• Haloalkyl indicates both branched and straight-chain alkyl groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms.
• haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
• Haloalkoxy indicates a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical).
• Hydroxyalkyf is an alkyl group as previously described, substituted with at least one hydroxyl subsitutuent.
• Aminoalkyl is an alkyl group as previously described, substituted with at least one amino subsitutuent.
• Halo or “halogen” indicates any of fluoro, chloro, bromo, and iodo.
• Aryl indicates aromatic groups containing only carbon in the aromatic ring or rings. Typical aryl groups contain 1 to 3 separate, fused, or pendant rings and from 6 to about 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 chosen from N, O, and S, to form, for example, a 3,4-methylenedioxy-phenyl group.
• Aryl groups include, for example, phenyl, naphthyl, including 1- naphthyl and 2- naphthyl, and bi-phenyl.
• a "Heterocyclic ring” is a saturated, unsaturated, or partially unsaturated (e.g. aromatic) ring containing 1 to 4 ring heteroatoms independently chosen from N, O, and S, or if indicated, N, O, S, and B, with remaining ring atoms being carbon.
• A" heterocyclic group" may contain 1 heterocyclic ring 1 ring of 3 to 7 ring atoms or 2 fused rings each containing 3 to 7 ring atoms with at least one ring being a heterocyclic ring.
• Heterocyclicoxy group is a monocyclic heterocyclic ring or a bicyclic heterocyclic group as described previously linked to the group it substitutes via an oxygen, -0-, linker.
• Heteroaryl indicates a stable monocyclic aromatic ring having the indicated number of ring atoms which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5- to 7-membered aromatic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon.
• Monocyclic heteroaryl groups typically have from 5 to 7 ring atoms.
• bicyclic heteroaryl groups are 9- to 10-membered heteroaryl groups, that is, groups containing 9 or 10 ring atoms in which one 5- to 7-member aromatic ring is fused to a second aromatic or non-aromatic ring.
• the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heteroaryl group is not more than 2. It is particularly preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
• heteroaryl groups include, but are not limited to, oxazolyl, pyranyl, pyrazinyl, pyrazolopyrimidinyl, pyrazolyl, pyridizinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienylpyrazolyl, thiophenyl, triazolyl, benzo[ ⁇ i]oxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxadiazolyl, dihydrobenzodioxynyl, furanyl, imidazolyl, indolyl, and isoxazolyl.
• Heteroaryloxy is a heteroaryl group as described bound to the group it substituted via an oxygen bridge.
• Heterocycloalkyl is a saturated ring group, having 1, 2, 3, or 4 heteroatoms independently chosen from N, S, and O, with remaining ring atoms being carbon.
• 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” indicates secondary or tertiary alkyl amino groups, wherein the alkyl groups are independently chosen alkyl groups, as defined herein, having the indicated number of carbon atoms. 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.
• substituted means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded.
• an oxo group substitutes aromatic moieties, the corresponding partially unsaturated ring replaces the aromatic ring.
• a pyridyl group substituted by oxo is a pyridone.
• a stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation into an effective therapeutic agent.
• substituents are named into the core structure. For example, it is to be understood that when aminoalkyl is listed as a possible substituent the point of attachment of this substituent to the core structure is in the alkyl portion.
• Suitable groups that may be present on a "substituted" or “optionally substituted” position include, but are not limited to, e.g., halogen; cyano; hydroxyl; nitro; azido; alkanoyl (such as a C 2 -C 6 alkanoyl group); carboxamide; alkyl groups (including cycloalkyl groups) having 1 to about 8 carbon atoms, or 1 to about 6 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 8, or 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 8, or from 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those having one or more thioether linkages and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; alkylsulfmyl groups including those having one or more
• "optionally substituted” includes one or more substituents independently chosen from halogen, hydroxyl, amino, cyano, -CHO, -COOH, -CONH 2 , Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, C 2 -C 6 alkanoyl, Ci-Cealkylester, (mono- and di-Ci-C 6 alkylamino)Co-C 2 alkyl, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
• a "dosage form” means a unit of administration of an active agent.
• dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, creams, ointments, suppositories, inhalable forms, transdermal forms, and the like.
• compositions are compositions comprising at least one active agent, such as a compound or salt of Formula I, and at least one other substance, such as a carrier. Pharmaceutical compositions optional contain one or more additional active agents. When specified, pharmaceutical compositions meet the U.S. FDA's GMP (good manufacturing practice) standards for human or non-human drugs. “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 a disorder, such as hepatitis C.

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