EA043505B1 - ARYL, HETEROARYL AND HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF COMPLEMENT MEDIATED DISORDERS - Google Patents

Description

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Claimed are compounds, methods of use and methods of producing complement factor D inhibitors, including formula I, or a pharmaceutically acceptable salt thereof, or a composition thereof, where R ¹² or R ¹³ on group A represents aryl, heteroaryl or heterocycle (R ³² ). The inhibitors described herein target factor D and inhibit or regulate the complement cascade at an early and significant point in the alternative complement pathway, and reduce the ability of factor D to modulate the classical and lectin complement pathways. The factor D inhibitors described herein are capable of reducing excessive complement activation, which is associated with certain autoimmune, inflammatory and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer.

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This application claims priority to US Provisional Application No. 61/944189, filed February 25, 2014, US Provisional Application No. 62/022916, filed July 10, 2014, and U.S. Provisional Application No. 62/046783, filed September 5, 2014. The entirety of each of these applications is incorporated herein by reference for all purposes.

State of the art

The complement system is a part of the innate immune system that does not adapt to changes during the host's life, but is recruited and used by the adaptive immune system. For example, it helps or complements the ability of antibodies and phagocytic cells to remove pathogens. This complex regulatory pathway allows for a rapid response to pathogenic organisms, protecting host cells from destruction. More than thirty proteins and protein fragments make up the complement system. These proteins act through opsonization (enhancing the phagocytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cell lysis (rupturing the membranes of foreign cells), and agglutination (clustering and binding pathogens together).

The complement system has three pathways: classical, alternative and lectin. Complement factor D plays an early and central role in the activation of the alternative pathway of the complement cascade. Activation of the alternative complement pathway is initiated by spontaneous hydrolysis of the thioester bond at C3 to produce C3( _H2O ), which binds to factor B to form the C3( _H2O )B complex. Complement factor D acts by cleaving factor B in the C3(H ₂ O)B complex to form Ba and Bb. The Bb fragment remains associated with C3( _H2O ) to form the alternative pathway C3 convertase C3( _H2O )Bb. In addition, C3b produced by any of the C3 convertases also binds to factor B to form C3bB, which cleaves factor D to produce a later step in the alternative C3 convertase pathway, C3bBb. This latter form of the alternative C3 convertase pathway may provide important downstream amplification throughout all three designated complement pathways, leading ultimately to the recruitment and assembly of additional factors in the complement cascade, including the cleavage of C5 into C5a and C5b. C5b functions in the assembly of factors C6, C7, C8 and C9 into a membrane attack complex that can kill pathogenic cells by cell lysis.

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

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

Paroxysmal nocturnal hemoglobinuria (PNH) is a benign, hematologic disorder characterized by the expansion of hematopoietic stem cells and progeny mature blood cells that are deficient in certain surface proteins. PNH erythrocytes fail to modulate their surface complement activation, resulting in the typical hallmark of PNH: chronic complement activation-mediated intravascular anemia. Currently, only one product, the anti-C5 monoclonal antibody eculizumab, has been approved in the United States for the treatment of PNH. However, many of the patients treated with eculizumab remain anemic, and many patients continue to require blood transfusions. In addition, eculizumab treatment requires intravenous injections throughout life. Thus, there is an unmet need for the development of new complement pathway inhibitors.

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

While initial attempts have been made to develop factor D inhibitors, 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.

US Patent No. 6653340 BioCryst Pharmaceuticals entitled Compounds Useful in the Complement, Coagulant and Kallikrein Pathways and Method for Their Preparation describes bicyclic ring fusion compounds that are potential factor D inhibitors. Development of the factor D inhibitor BCX1470 was discontinued due to lack of specificity and short half-life of the compound .

Novartis patent publication PCT WO2012/093101 entitled Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration describes certain factor D inhibitors.

Novartis PCT patent publications WO2014/002057 entitled Pyrrolidine derivatives and their use as complement pathway modulators and WO2014/009833 entitled Complement pathway modulators and their use 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.

Bristol-Myers Squibb PCT patent publication WO2004/045518 entitled Urea-Linked Open-Chain Prolyl Modulators with Androgen Receptor Function describes urea- and thiourea-linked open-chain prolyl compounds for the treatment of androgen receptor-associated conditions such as age-related diseases. , for example, sarcopenia.

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

In the PCT patent publication Ferring B.V. and Yamanouchi Pharmaceutical Co. LTD. WO1993/020099, entitled CCK and/or gastrin receptor ligands, describes compounds with a proline-like core and heterocyclic substituents linked to the proline core via amide bonds for the treatment of, for example, stomach disorders or pain.

Alexion Pharmaceuticals PCT patent publication WO1995/029697, entitled Methods and compositions for treating glomerulonephritis and other inflammatory diseases, discloses anti-C5 complement pathway antibodies for the treatment of glomerulonephritis and inflammatory conditions involving abnormal activation of the complement system. Alexion Pharmaceutical's anti-C5 antibody eculizumab (Soliris®) is currently the only complement-specific antibody on the market and represents the first and only approved treatment for paroxysmal nocturnal hemoglobinuria (PNH).

Compounds that mediate the complement pathway, and, for example, act as factor D inhibitors, are needed to treat disorders in the recipient, including humans, associated with misregulation of the complement cascade.

The essence of the invention

It has been found that a compound of formula I, or a pharmaceutically acceptable salt or composition thereof, wherein R ¹² or R ¹³ on group A is aryl, heteroaryl or heterocycle, is an excellent complement factor D inhibitor.

In one embodiment, the invention provides a method of treating a disorder associated with dysfunction, including hyperactivity, of the complement pathway, which comprises administering 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.

In one embodiment of the invention, the disorder is associated with an alternative pathway of the complement cascade. In yet another embodiment of the invention, the disorder is associated with the classical complement pathway. In a further embodiment of the invention, the disorder is associated with the complement lectin pathway. Factor D inhibitors provided herein can thus attenuate or inhibit deleterious complement activity in a recipient by administering an effective amount in an appropriate manner to the recipient in need thereof.

Specific embodiments of the present invention are directed to certain displays

- 2 043505 research of diseases. In one embodiment of the invention, a method of treating paroxysmal nocturnal hemoglobinuria (PNH) comprises administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method of treating age-related macular degeneration (AMD), which includes administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method of treating rheumatoid arthritis, which includes administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method of treating multiple sclerosis, which includes administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

In other embodiments, an active compound as claimed herein may be used to treat or prevent a disorder in a recipient mediated by complement factor D or excessive or detrimental amounts of the C3 amplification loop of the complement pathway. By way of example, the present invention includes methods for treating or preventing complement-related disorders that are induced by antibody-antigen interactions, a component of an immune or autoimmune disorder, or ischemic injury. The invention also provides methods for reducing inflammation or an immune response, including an autoimmune response, that is mediated or influenced by factor D.

The present invention relates to compounds of formula I

and pharmaceutically acceptable salts thereof and compositions therewith, in which:

Q ¹

Q ²

Q ³

X ¹

C=C; and is N(R1) or C(R ¹ R ¹ );

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

represents N(R ³ ), S or C(R ³ R ^3' );

and X ² are independently N, CH, or CZ, or X ¹ and X ² together are where Q ¹ , Q ² , Q ³ , X ¹ and X ² are selected to result in stable compounds. 2-Q ³

I\4

Non-limiting examples of the ring are shown below (any of which may be otherwise substituted with R ¹ , R ¹ , R ² , R ² , R ³ and R ³ ) as described in more detail below.

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where q is 0, 1, 2 or 3, and r is 1, 2 or 3.

R and R' are independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, where each group may be optionally substituted, or any other substituent group herein that provides the desired properties. In some embodiments of the invention, the ring includes one or more chiral carbon atoms. The invention includes embodiments in which the chiral carbon may be present as an enantiomer or mixtures of enantiomers, including a racemic mixture. Where the ring includes more than one stereocenter, all enantiomers and diastereomers are included in the invention as individual examples.

Z represents F,'Cl, NH ₂ , CH ₃ , CH2D, CHD2 or CD ₃ .

R ¹ , R ¹ , R ² , R ² , R ³ and R ³ are independently selected on a case-by-case basis as needed and only when leading to stable compounds from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C2-C6alkynyl, C2-C6alkanoyl, C1-C6thioalkyl, hydroxyC1-C6alkyl, aminoC1-C6alkyl, -C0-C4alkyl-NR ⁹ R ¹⁰ , -C(O)OR ⁹ , -OC(O)R ⁹ , -NR ⁹ C(O)R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ , -NR ⁹ C(O)OR ¹⁰ , C1-C2haloalkyl and C1-C2haloalkoxy, where R ⁹ and R ¹⁰ are independently selected in each case from hydrogen, C1-C ₆ alkyl, (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl) and -O-C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl).

In alternative embodiments of the invention, R ¹ and R ¹ or R ³ and R ³ can be taken together to form a 3-6 membered carbocyclic spiro ring or a 3-6 membered heterocyclic spiro ring containing 1 or 2 heteroatoms, independently selected from N, O or S; R ² and R ² can be taken together to form a 3-6 membered carbocyclic spiro ring; or R ² and R ² can be taken together to form a 3-6 membered heterocyclic spiro ring; each spiro ring may be unsubstituted or substituted with 1 or more substituents independently selected from halogen (and in particular F), hydroxyl, cyano, -COOH, C1-C ₄ alkyl (including, in particular, methyl) , C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C1-C ₄ alkoxy, C ₂ -C ₄ alkanoyl, hydroxyC1-C ₄ alkyl, (mono- and di-C1-C ₄ alkylamino)C ₀ -C ₄ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl),

-O-C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

In alternative embodiments of the invention, R ¹ and R ² can be taken together to form a 3-membered carbocyclic ring; R ¹ and R ² can be taken together to form a 4-6 membered carbocyclic or aryl ring, or a 4-6 membered heterocyclic or heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, O and S; or R ² and R ³ , when bonded to adjacent carbon atoms, can be taken together to form a 3-6 membered carbocyclic or aryl ring, or a 3-6 membered heterocyclic or heteroaryl ring; each of the rings may be unsubstituted or substituted with 1 or more substituents independently selected from halogen (and in particular F), hydroxyl, cyano, -COOH, C1-C ₄ alkyl (including, in particular, methyl), C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C1-C ₄ alkoxy, C ₂ -C ₄ alkanoyl, hydroxyC1-C ₄ alkyl, (mono- and di-C1-C ₄ alkylamino)C ₀ -C ₄ alkyl , -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -O -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

In alternative embodiments of the invention, R ¹ and R ¹ , R ² and R ² , or R ³ and R ³ may be taken together to form a carbonyl group. In alternative embodiments of the invention, R ¹ and R ² or R ² and R ³ can be taken together to form a carbon-carbon double bond.

A represents a group selected from:

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R ⁴ is selected from -CHO, -CONH2, C2-C6alkanoyl, hydrogen, -SO2NH2, -C(CH2)2F, -CH(CF ₃ )NH2, C1-C6alkyl, -C ₀ -C ₄ alkyl(C ₃ -C7cycloalkyl ), -C(O)C ₀ -C ₂ alkyl (C ₃ -C ₇ cycloalkyl),

each of R ⁴ other than hydrogen, -CHO and -CONH2 is unsubstituted or substituted by one or more of amino, imino, halogen, hydroxyl, cyano, cyanoimino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C1-C ₄ alkylamino), C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

R ⁵ and R6 are independently selected from -CHO, -C(O)NH2, -C(O)NH(CH3), C2-C6alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, -COOH, -SO2NH2, vinyl, C1 -C6alkyl (including methyl), C2-C6alkenyl, C1-C6alkoxy, -C0-C4alkyl(C3-C7cycloalkyl), -C(O)C0-C4alkyl(C3-C7cycloalkyl), -P(O)(OR ⁹ )2, -OC(O)R ⁹ , -C(O)OR ⁹ , C(O)N(CH ₂ CH ₂ R ⁹ )(R ¹⁰ ), -NR ⁹ C(O)R ¹⁰ , phenyl or 5 -6-membered heteroaryl.

Each R ⁵ and R ⁶ other than hydrogen, hydroxyl, cyano and -COOH is unsubstituted or optionally substituted. For example, R ⁵ and R ⁶ other than hydrogen, hydroxyl, cyano and -COOH may be substituted with one or more substituents independently selected from halogen, hydroxyl, amino, imino, cyano, cyanoimino, C ₁ -C ₂ alkyl, C1 -C ₄ alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C1-C ₄ alkylamino), C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

R ⁶ is hydrogen, halogen, hydroxyl, C1- _C4 alkyl, _-C0 - _C4 alkyl( _C3 - _C7 cycloalkyl) or

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C1- _C4 alkoxy; or R ⁶ and R ⁶ can be taken together to form an oxo, vinyl or imino group.

R ⁷ represents hydrogen, C ₁ -C ₆ alkyl or -C ₀ -C ₄ alkyl (C ₃ -C7 cycloalkyl).

R8 and R8 are independently selected from hydrogen, halogen, hydroxyl, _C1 - _C6 alkyl, _-C0 - _C4 alkyl( _C3 - _C7 cycloalkyl), _C1 - _C6 alkoxy and (C1- _C4 alkylamino)C ₀ -C2alkyl; or R8 and R8 taken together form an oxo group; or R8 and R8 can be taken together with the carbon atom to which they are bonded to form a 3-membered carbocyclic ring.

R ¹⁶ is absent or may include one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ alkyl, C 2 -C ₆ alkenyl, C 2 -C ₆ alkanoyl, C ₁ -C ₆ alkoxy, -C ₀ -C ₄ alkyl (mono- and di-C1-C ₆ alkylamino), -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C ₂ haloalkyl and C 1-C ₂ haloalkoxy.

R ¹⁹ represents hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, -SO2C1-C6alkyl, (mono-di-C1-C6alkylamino)C1-C4alkyl, -C0-C4alkyl(C3-C7cycloalkyl), -C0-C4alkyl( C3-C7heterocycloalkyl), -C0-C4alkyl(aryl), C0-C4alkyl(heteroaryl), and where R ¹⁹ other than hydrogen is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, -COOH and -C(O)OC1-C4alkyl.

X ¹¹ represents N or CR ¹¹ .

X ¹² represents N or CR ¹² .

X ¹³ represents N or CR ¹³ .

X ¹⁴ represents N or CR ¹⁴ .

At most 2 of X ¹¹ , X ¹² , X ¹³ and X ¹⁴ are N.

One of R ¹² and R ¹³ is selected from R ³¹ , and the other of R ¹² and R ¹³ is selected from R ³² . In an alternative embodiment of the invention, R ¹² and R ¹³ are each independently selected from the remainder R ³² .

R ³¹ is selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, -COOH, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C6alkyl, -C0-C4alkyl(C3-C7cycloalkyl), C2-C6alkenyl, C2-C6alkanoyl, C1 -C6alkoxy, C2-C6alkenyloxy, -C(O)OR ⁹ , C1-C ₆ thioalkyl, -C ₀ -C ₄ alkyl-NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO2R ⁹ , -SO2NR9R ¹⁰ , -OC(O)R ⁹ and -C(NR ⁹ )NR ⁹ R ¹⁰ , each of R ³¹ other than hydrogen, halogen, hydroxyl, nitro, cyano, C1-C2haloalkyl and C1-C2haloalkoxy, is unsubstituted or substituted one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, -COOH, -CONH2 C1-C2haloalkyl and C1-C2haloalkoxy, and each of R ³¹ is also optionally substituted with one substituent selected from phenyl and 4-7- a member heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein the phenyl or 4-7-membered heterocycle is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C1-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkoxy, (mono- and di-C1C ₆ alkylamino) C ₀ -C ₄ alkyl, C ₁ -C ₆ alkyl ether, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C ₂ haloalkyl and C1C2 haloalkoxy;

R ³² is selected from aryl; saturated or unsaturated heterocycle (for example, a 5-6 membered ring having 1, 2 or 3 heteroatoms independently selected from N, O and S), where the heterocycle is linked through a carbon atom in the heterocyclic ring to the carbon atom of ring A at the R ¹² position or R ¹³ ; and heteroaryl (eg, a 5-6 membered ring having 1, 2 or 3 heteroatoms independently selected from N, O and S), wherein the aryl, heterocycle or heteroaryl ring may be optionally substituted.

R ¹¹ , R ¹⁴ and R ¹⁵ are independently selected in each case from hydrogen, halogen, hydroxyl, nitro, cyano, -O(PO)(OR ⁹ )2, -(PO)(OR ⁹ )2, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ alkenyl(aryl), C2-C6alkenyl(cycloalkyl), C2-C6alkenyl(heterocycle), C2-C6alkenyl(heteroaryl), C2-C6alkynyl , C2-C6alkynyl(aryl), C2-C6alkynyl(cycloalkyl), C2- _C6alkynyl (heterocycle), C2-C6alkynyl(heteroaryl), _C2 -C6alkanoyl, _C1 - _C6alkoxy , _C1 - _C6thioalkyl , -C ₀ -C ₄ alkyl (mono- and di-C1-C ₆ alkylamino), -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -C ₀ -C ₄ alkoxy (C ₃ -C ₇ cycloalkyl ), C ₁ -C ₂ haloalkyl and C1C2 haloalkoxy.

L represents a bond or is selected from formulas

where R ¹⁷ represents hydrogen, C ₁ -C ₆ alkyl or -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), and R ¹⁸ and R ¹⁸ are independently selected from hydrogen, halogen, hydroxymethyl and methyl; and m is 0, 1, 2 or 3.

B is a monocyclic or bicyclic carbocyclic; a monocyclic or bicyclic carbocyclooxy 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 in the ring; C2-C6alkenyl; C2-C6alkynyl; -(C0-C4-alkyl)(aryl); -(C0-C4-alkyl)(heteroaryl); or -(C0-C4-alkyl)(biphenyl).

Each of B is unsubstituted or substituted with one or more substituents independently selected from R ³³ and R ³⁴ , and 0 or 1 substituent selected from R ³⁵ and R ³⁶ .

R ³³ is independently selected from halogen, hydroxyl, -COOH, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkanoyl,

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C1-Cbalkoxy, -C ₀ -C ₄ alkyl-NR ⁹ R ¹⁰ , -SO2R ⁹ , C1-C2haloalkyl and C1-C2haloalkoxy;

R ³⁴ is independently selected from nitro, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ thioalkyl,

-JC3-C7Cycloalkyl, -B(OH)2, -JC(O)NR ⁹ R ²³ , -JOSO2OR ²¹ , -C(O)(CH2)i-4S(O)R ²¹ , -O(CH2)i— 4S(O)NR ²¹ R ²² ,

-JOP(O)(OR ²¹ )(OR ²² ), -JP(O)(OR ²¹ )(OR ²² ), -JOP(O)(OR ²¹ )R ²² , JP(O)(OR ²¹ )R ²² , -JOP(O)R ²¹ R ²² , -JP(O)R ²¹ R ²² ,

-JSP(O)(OR ²¹ )(OR ²² ), -JSP(O)(OR ²¹ )(R ²² ), -JSP(O)(R ²¹ )(R ²² ), -JNR ⁹ P(O)( NHR ²¹ )(NHR ²² ),

-JNR ⁹ P(O)(OR ²¹ )(NHR ²² ), JNR ⁹ P(O)(OR ²¹ )(OR ²² ), -JC(S)R ²¹ , -JNR21SO2R ²² , -JNR ⁹ S(O) NR10R ²² , -JNR ⁹ SO2NR ¹⁰ R ²² , -JSO2NR9COR ²² , -JSO2NR ⁹ CONR ²¹ R ²² , -JNR21SO2R ²² , -JC(O)NR ²¹ SO2R ²² , -JC(NH2)NR ²² , -JC(NH2) NR ⁹ S(O)2R ²² , -JOC(O)NR ²¹ R ²² , -JNR ²¹ C(O)OR ²² , -JNR ²¹ OC(O)R ²² , -(CH2)1-4C(O)NR ²¹ R ²² , -JC(O)R ²⁴ R ²⁵ , -JNR ⁹ C(O)R ²¹ , -JC(O)R ²¹ , -JNR ⁹ C(O)NR ¹⁰ R ²² , -CCR ²¹ , -( CH2)1-4OC(O)R ²¹ and -JC(O)OR ²³ ; each of R ³⁴ may be unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH) ₂ , -Si(CH ₃ ) ₃ , -COOH, -CONH2, -P(O)(OH) ₂ , Ci-Cbalkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C6αalkoxy, -C ₀ -C ₂ alkyl (mono- and di-C1- C ₄ alkylamino), C ₁ -C ₆ alkylester, C 1 -C ₄ alkylamino, C 1 -C ₄ hydroxyalkyl, C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

R ³⁵ is independently selected from naphthyl, naphthyloxy, indanyl, (4-7 membered heterocycloalkyl)C0C4alkyl containing 1 or 2 heteroatoms selected from N, O and S, and a bicyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and containing from 4 to 7 ring atoms in each ring; each of R ³⁵ is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C1- _C6 alkyl _{, C2} - _C6 alkenyl, _C2C6 alkanoyl, _C1 - _C6 alkoxy, ( mono- and di-C1-C ₆ alkylamino) C ₀ -C ₄ alkyl, C ₁ -C ₆ alkyl ether, -CoC ₄ alkyl (C ₃ -C ₇ cycloalkyl), -SO2R ⁹ , C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

R ³⁶ is independently selected from tetrazolyl, (phenyl)C0-C2alkyl, (phenyl)C1-C2αalkoxy, phenoxy and 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, B and S, each of R ³⁶ is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C1- _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkanoyl, _C1 - _C6 alkoxy, (mono- and diC ₁ -C ₆ alkylamino)C ₀ -C ₄ alkyl, C ₁ -C ₆ alkyl ether, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -SO2R ⁹ ,

-OSi(CH ₃ ) ₂ C(CH ₃ ) ₃ , -Si(CH ₃ ) ₂ C(CH ₃ ) ₃ , C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

R ²¹ and R ²² are independently selected in each case from hydrogen, hydroxyl, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl, (phenyl)C ₀ -C ₄ alkyl, -C ₁ -C ₄ alkylOS(O)OS ₁ -C ₆ alkyl, -C ₁ -C ₄ alkylOS(O)C ₁ -C ₆ -alkyl, -C ₁ -C ₄ alkylC(O)OS ₁ -C ₆ alkyl, (4-7-membered heterocycloalkyl)C ₀ -C ₄ alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S, and (5 - or a 6-membered unsaturated or aromatic heterocycle)C ₀ -C ₄ -alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S, and each of R ²¹ and R ²² may be optionally substituted.

R ²³ is independently selected in each case from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, (aryl)C ₀ -C ₄ alkyl, (C3-C7cycloalkyl)C0-C4alkyl, (phenyl)C0-C4alkyl, (4 -7-membered heterocycloalkyl)C0-C4alkyl having 1, 2, or 3 heteroatoms independently selected from N, O and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C0-C4alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and each R ²³ may be optionally substituted.

R ²⁴ and R ²⁵ together with the nitrogen atom to which they are attached form a 4-7 membered monocyclic heterocycloalkyl group or a 6-10 membered bicyclic heterocyclic group having fused, spiro or bridged rings, and each of R ²⁴ and R ²⁵ may optionally be substituted.

J is independently selected in each case from covalent bond, C ₁ -C ₄ alkylene, -OC ₁ -C ₄ alkylene, C 2 -C 4 alkenylene and C 2 -C 4 alkynylene.

Also disclosed are pharmaceutical compositions containing a compound or salt of Formula I together with a pharmaceutically acceptable carrier.

Disclosed are methods of treating or preventing disorders mediated by factor D of the complement cascade, including, but not limited to, age-related macular degeneration (AMD), retinal degeneration, other ophthalmic diseases (eg, geographic atrophy), paroxysmal nocturnal hemoglobinuria (PNH) , multiple sclerosis (MS), arthritis, including rheumatoid arthritis (RA), a respiratory disease or a cardiovascular disease, comprising administering a therapeutically effective amount of a compound or salt of Formula I to a recipient, including a human in need of such treatment.

In another embodiment, the invention provides an effective amount of an active factor D inhibitory compound for the treatment of an inflammatory or immune disorder, including an autoimmune disorder, that is mediated or influenced by factor D. In an alternative embodiment of the invention, a compound of formula I can be used to treat a disorder mediated by complement, regardless of whether it acts through Factor D.

The present invention includes at least the following features:

(a) a compound of formula I, as described herein, and its pharmaceutically acceptable salts and prodrugs (each of which and all subgenera and species considered individually

- 7 043505 and specifically described);

(b) formula I, as described herein, and pharmaceutically acceptable salts and prodrugs thereof, for use in the treatment or prevention of disorders mediated by complement and, for example, cascade factor D, including age-related macular degeneration (AMD), degeneration retina, paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis (MS) and rheumatoid arthritis (RA) and other disorders described hereinafter;

(c) the use of formula I and its pharmaceutically acceptable salts and prodrugs in the manufacture of a medicament for use in the treatment or prevention of disorders mediated by complement and, for example, cascade factor D, including age-related macular degeneration (AMD), retinal degeneration, paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis (MS) and rheumatoid arthritis (RA) and other disorders described hereinafter;

(d) a method of producing a medicinal product intended for therapeutic use for the treatment or prevention of the treatment or prevention of disorders mediated by factor D of the complement cascade, including age-related macular degeneration (AMD), retinal degeneration, paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis ( MS) and rheumatoid arthritis (RA) and other disorders described hereinafter, characterized in that Formula I described herein is used in the preparation;

(e) a pharmaceutical composition comprising an effective treatment amount of Formula I or a pharmaceutically acceptable salt or prodrug thereof together with a pharmaceutically acceptable carrier or diluent;

(f) formula I, as described herein, in substantially pure form, including substantially isolated from other chemical compounds (eg, at least 90 or 95%);

(g) methods for preparing compounds of formula I and their salts, compositions, dosage forms; and (h) methods for preparing therapeutic products that contain an effective amount of Formula I, as described herein.

Detailed Description of the Invention

I. Terminology.

Connections are described using standard nomenclature. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention belongs.

The compounds in any of the formulas described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates, and other isomers, such as rotamers, as if each were 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 otherwise clearly inconsistent with the context in which the phrase is given. Formula 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 otherwise clearly contradicted the context in which this phrase is given.

The terms a and an do not denote a limitation in quantity, but rather denote the presence of at least one of those described. The term or means both/or. The indication of ranges of values is intended only as a shorthand way of referring individually to each individual value falling within the range, unless otherwise specified herein, and each individual value is included in the description as if it were individually stated herein. The end values of all ranges are included within the range limits and are combined independently. All methods described herein can be performed in an appropriate order, unless otherwise indicated herein or otherwise clearly contrary to the context. The use of examples or illustrative expressions (eg, such) is intended to better illustrate the invention only and is not intended to limit the scope of the invention unless otherwise stated. Unless otherwise specified, technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention belongs.

The present invention includes compounds of formula I and the use of compounds with at least one desired isotopic substitution of an atom in an amount that is higher than the natural abundance of the isotope, i.e. enriched. Isotopes are atoms that have the same atomic number but different mass numbers, i.e. same number of protons, but different number of neutrons.

Examples of isotopes that may be included in the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ^2H , ^3H , ^nC , ^13C , ^14C , ^15N , ^{18F 31} P, ³² P, ³⁵ S, ³⁶ Cl, ¹²⁵ I, respectively. The invention includes isotopically modified compounds of formula I. In one embodiment of the invention, the isotopically labeled 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 like positron emission tomography

- 8 043505 (PET) or single photon emission computed tomography (SPECT), including analyzes of tissue distribution of drugs or substrates, or in radioactive treatment of patients. In particular, a compound labeled with ¹⁸ F may be particularly desirable for PET or SPECT studies. The isotope-labeled compounds of this invention and their prodrugs generally can be prepared by following the procedures described in the Schemes or Examples, and the drugs described below can be prepared by replacing the readily available isotope-labeled reagent with a non-isotope-labeled reagent.

By way of general example and not limitation, isotopes of hydrogen, such as deuterium ( ^2H ) and tritium ( ^3H ), can be used at any position in the described structures to achieve the desired result. Alternatively or in addition, carbon isotopes may be used, for example, ¹³ C and ¹⁴ C. In one embodiment of the invention, isotopic substitution is the substitution of deuterium for hydrogen at one or more positions of the molecule to improve the effectiveness of the drug, for example, pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, deuterium may be bonded to a carbon at the site of bond breaking during metabolism (α-deuterium kinetic isotope effect) or at or near the bond breaking site (β-deuterium kinetic isotope effect).

Isotopic substitutions, such as deuterium substitutions, can be partial or complete. Partial substitution by deuterium means that at least one hydrogen is replaced by deuterium. In some embodiments, the isotope is enriched by 90, 95, or 99% or more in the isotope at any position of interest. In one embodiment of the invention, the desired position is 90, 95 or 99% deuterium enriched. Unless otherwise stated, fortification at any position is greater than the natural content and is sufficient to change the detectable property of the drug in the human body.

In one embodiment of the invention, the replacement of a hydrogen atom with a deuterium atom occurs within the R group substituent in the region of the LB fragment. In one embodiment of the invention, the replacement of a hydrogen atom with a deuterium atom occurs within a group R selected from any of R ¹⁸ , R ¹⁸ , R ³³ , R ³⁴ , R ³⁵ and/or R ³⁶ . In one embodiment of the invention, the replacement of a hydrogen atom with a deuterium atom occurs within the R group substituent in the region of the A-carbonyl fragment. In one embodiment of the invention, the replacement of a hydrogen atom with ^a deuterium atom occurs in R ⁴ , R ⁵ , R ⁶ , R ⁶ , R ⁷ , R ⁸ , R ⁸ ', R ¹¹ , R 12, R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁹ , R ²¹ , R ²² , R ²³ , R ³¹ and R ³² . In other embodiments, certain substituents on the proline ring are selectively deuterated. For example, in one embodiment of the invention, the replacement of a hydrogen atom with a deuterium atom occurs in R, R', ^R1 , ^R1 , ^R2 , ^R2' , ^R3 and/or ^R3' . In one embodiment of the invention, for example, when any of the R ring substituents on proline is methyl or methoxy, the alkyl moiety is optionally deuterated, eg CD ₃ or OCD ₃ . In some other embodiments, when two proline ring substituents are combined to form a cyclopropyl ring, the unsubstituted methylene carbon is deuterated.

Substitution of a hydrogen atom by a deuterium atom occurs within an R group when at least one of the variables in the R group is hydrogen (eg, ^2H or D) or alkyl (eg, CD ₃ ). For example, when any of the R groups is or contains, for example, by substitution, methyl or ethyl, the alkyl moiety is typically deuterated, for example, CD ₃ , CH ₂ CD ₃ or CD2CD3.

The compound of the present invention can form a solvate with solvents (including water). Thus, in one embodiment, the invention includes a solvated form of the active compound. The term solvate refers to the molecular complex of a compound of the present invention (including its salts) with one or more solvent molecules. Examples of solvents include water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents. The term hydrate refers to a molecular complex containing a compound of the invention and water. Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent may be isotopically substituted, for example, D ₂ O, d ₆ acetone, d ₆ -DMSO. The solvate can be in liquid or solid form.

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

The term substituted, as used herein, means that any one or more hydrogen atoms of a specified atom or group are replaced by a moiety selected from the specified group, provided that the normal valency of the specified atom is not exceeded. For example, when the substituent is oxo (ie =O), then two hydrogen atoms per atom are replaced. When an oxo group replaces two hydrogen atoms in an aromatic moiety, a corresponding partially unsaturated ring replaces the aromatic ring. For example, a pyridyl group substituted with an oxo group is pyridone. Combinations of substituents and/or variables are only allowed if

- 9 043505 such combinations lead to stable compounds or useful synthetic intermediates.

A stable compound or stable structure refers to a compound resulting in a compound that can be isolated and formulated into a dosage form with a shelf life of at least one month.

At the substituted or optionally substituted position, any suitable group may be present that forms a stable molecule and achieves the desired purpose of the invention, and includes, but is not limited to, for example, halogen (which may independently be F, Cl, Br or I); cyano; hydroxyl; nitro; azido; alkanoyl (such as a C2-Sbalkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; alkylthio, including those having one or more thioether linkages; alkylsulfinyl; alkylsulfonyl groups, including those having one or more sulfonyl bonds; aminoalkyl groups, including groups having one or more N atoms; aryl (eg, phenyl, biphenyl, naphthyl or the like, each ring being either substituted or unsubstituted aromatic); arylalkyl having, for example, from 1 to 3 individual or fused rings and from 6 to about 14 or 18 ring carbon atoms, benzyl being an example of an arylalkyl group; arylalkoxy, for example, having from 1 to 3 separate or fused rings with benzyloxy, which is an example of an arylalkoxy group; or a saturated, unsaturated, or aromatic heterocyclic group having from 1 to 3 separate or fused rings with one or more N, O or S atoms, for example, coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl and pyrrolidinyl. Such heterocyclic groups may be further substituted, for example, hydroxy, alkyl, alkoxy, halogen and amino. In some embodiments, optionally substituted includes one or more substituents independently selected from halogen, hydroxyl, amino, cyano, -CHO, -COOH, -CONH2, _{C1- C6} alkyl, C2- _C6 alkenyl, C2- _C6 alkynyl, -C ₁ -C ₆ alkoxy, C2-C ₆ alkanoyl, C ₁ -C ₆ alkyl ether, (mono- and di-C1-C ₆ alkylamino)C ₀ -C2 alkyl, C ₁ -C ₂ haloalkyl, hydroxyC1-C ₆ alkyl, ester, carbamate, urea, sulfonamide, -C1-C ₆ alkyl(heterocyclo), C1-C ₆ alkyl(heteroaryl), -C1-C ₆ alkyl(C ₃ -C7cycloalkyl), O-C1-C ₆ alkyl(C ₃ C7cycloalkyl), B(OH) ₂ , phosphate, phosphonate and C ₁ -C ₂ haloalkoxy.

Alkyl is a branched or straight chain saturated aliphatic hydrocarbon group. In one embodiment of the invention, alkyl contains from 1 to about 12 carbon atoms, more typically from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one embodiment of the invention, alkyl contains from 1 to about 8 carbon atoms. In some embodiments, alkyl is C1-C2, _C1 - _C3 , or Ci- _C6 . Specific ranges, as used herein, indicate an alkyl group having each member of the range described as a separate species. For example, the term C1- _C6 alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5 or 6 carbon atoms, and means that each is described as a distinct species. For example, the term C1- _C4 alkyl as used herein indicates a straight or branched alkyl group having 1, 2, 3 or 4 carbon atoms and means that each is described as a distinct species. When _{C0 -C} alkyl is used herein in combination with another group, for example, (C3-C7cycloalkyl)C0-C4alkyl or -C0-C4alkyl(C3-C7cycloalkyl), then said group, in this case cycloalkyl, is either directly linked a single covalent bond (C0alkyl), or attached by an alkyl chain, in this case with 1, 2, 3 or 4 carbon atoms. Alkyls can also be attached through other groups such as heteroatoms, as in -O- _C0 - _C4alkyl ( _C3 - _C7cycloalkyl ). Examples of alkyl include, but are not limited to, methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, t-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane and 2,3-dimethylbutane. In one embodiment of the invention, the alkyl group is optionally substituted, as described above.

Alkenyl is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds which may be in a stable position on the chain. Non-limiting examples are C ₂ -C ₈ alkenyl, C ₂ -C ₆ alkenyl and C ₂ -C ₄ alkenyl. Specific ranges, as used herein, indicate an alkenyl group having each member of the range described as a separate species, as described above for the alkyl moiety. Examples of alkenyl include, but are not limited to, ethenyl and propenyl. In one embodiment of the invention, the alkenyl group is optionally substituted, as described above.

Alkynyl is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, which can be at any stable position on the chain, for example, C ₂ -C ₈ alkynyl or C ₂ -C ₆ alkynyl. Specific ranges, as used herein, indicate an alkynyl group having each member of

- 10 043505 range, described as a separate species, as described above for the alkyl residue.

Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl,

1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5hexynyl. In one embodiment of the invention, the alkynyl group is optionally substituted as described above.

Alkylene means a divalent saturated hydrocarbon. Alkylenes, for example, may be 1 to 8 carbons, 1 to 6 carbons, or a specified number of carbon atoms, for example, C1- _C4 alkylene, _C1 - _C3 alkylene, or _C1 - _C2 alkylene.

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

Alkynylene is a divalent hydrocarbon having at least one carbon-carbon triple bond. Alkenylenes, for example, may be 2 to 8 carbon, 2 to 6 carbon, or a specified number of carbon atoms, for example, C ₂ -C ₄ alkynylene.

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

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

An alkanoyl is an alkyl group, as defined above, covalently linked through a carbonyl (C=O) bridge. The carbon of the carbonyl group is one of the carbon atoms, that is, C ₂ alkanoyl is a CH ₃ (C=O)- group. In one embodiment of the invention, the alkanoyl group is optionally substituted as described above.

An alkyl ether is an alkyl group, as defined herein, covalently linked through an ether bond. The ether bond can be in one orientation or another, for example, a group of the formula -O(C=O)alkyl or a group of the formula -(C=O)Oalkyl.

The amide or carboxamide is -C(O)NR ^a R ^b where R ^a and R ^b are each independently selected from hydrogen, alkyl, eg C ₁ -C ₆ α alkyl, alkenyl, eg C ₂ -C ₆ alkenyl, alkynyl , for example, C ₂ -C ₆ alkynyl, -Co-C4alkyl (C ₃ -C7cycloalkyl), -Co-C4alkyl (C ₃ -C7heterocycloalkyl),

-Co-C ₄ alkyl(aryl) and -C ₀ -C ₄ alkyl(heteroaryl); or together with the nitrogen to which they are attached, R ^a and R ^b can form a C3-C7 heterocyclic ring. In one embodiment of the invention, the group R ^a and R ^b are each independently optionally substituted as described above.

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

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

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

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

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

Aminoalkyl is an alkyl group, as previously described, substituted by at least

- 11 043505 with at least one amino acid substituent.

Halo or halogen means independently any of fluorine, chlorine, bromine and iodine.

Aryl means an aromatic group containing only carbon in the aromatic ring or rings. In one embodiment of the invention, aryl groups contain from 1 to 3 separate or fused rings and from 6 to about 14 or 18 ring atoms without a heteroatom as a ring member. When indicated, such aryl groups may be further substituted with carbon atoms or non-carbon atoms or groups. Such substitution may involve condensation with a 5 to 7 membered saturated cyclic group, which optionally contains 1 or 2 heteroatoms independently selected from N, O and S, to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment of the invention, the aryl groups are pendant. An example of a pendant ring is a phenyl group substituted by a phenyl group. In one embodiment of the invention, the aryl group is optionally substituted as described above.

The term heterocycle or heterocyclic ring, as used herein, refers to a saturated or partially unsaturated (i.e., having one or more double and/or triple bonds on the ring without aromaticity) carbocyclic radical of from 3 to about 12 or more, as typically from 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, and the remaining ring atoms are C, wherein one or more ring atoms atoms is optionally substituted independently with one or more of the substituents described above. The 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 ( from 4 to 9 carbon atoms and from 1 to 6 heteroatoms selected from N, O, P and S), for example: bicyclo[4,5], [5,5], [5,6] or [6,6] system ]. In one embodiment of the invention, the single heteroatom is nitrogen. In one embodiment of the invention, the single heteroatom is oxygen. In one embodiment of the invention, the single heteroatom is sulfur. Heterocycles are described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7 and 9; The Chemistry of Heterocyclic Compounds, A series of Monographs (John Wiley & Sons, New York, 1950 to present), especially volumes 13, 14, 16, 19 and 28; and in J. Am. Chem. Soc. (1960) 82:5566. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, piperidonyl, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, tietanyl, homopi peridinil, oxepanil, tiepanil, oxazepinil, diazepinil . ylimidazolinyl, imidazolidinyl, 2-oxa -5-azabicyclo[2.2.2]octane, 3-oxa-8azabicyclo[3.2.1]octane, 8-oxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane , 2-oxa-5azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl, quinolizinyl, N-pyridylurea and pyrrolopyrimidine. Spiro residues are also included within the scope of this definition. Examples of a heterocyclic group in which 1 or 2 ring carbon atoms are replaced by oxo (=O) moieties are pyrimidinonyl and 1,1dioxothiomorpholinyl. Heterocyclic groups as used herein are optionally independently substituted with one or more substituents described herein.

A heterocyclicoxy group is a monocyclic heterocyclic ring or bicyclic heterocyclic group, as previously described, linked to the group it replaces via an oxygen, -0-, linker.

Heteroaryl indicates a stable monocyclic aromatic ring that contains from 1 to 3, or in some embodiments from 1 to 2 heteroatoms selected from N, O and S, the remaining ring atoms being carbon, or a stable bicyclic or tricyclic system, containing at least one 5-7 membered aromatic ring that contains from 1 to 3 or in some embodiments from 1 to 2 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. In one embodiment of the invention, the single heteroatom is nitrogen. In one embodiment of the invention, the single heteroatom is oxygen. In one embodiment of the invention, the single heteroatom is sulfur. Monocyclic heteroaryl groups typically have 5 to 7 ring atoms. In some embodiments, the bicyclic heteroaryl groups are 9-10 membered heteroaryl groups, that is, groups containing 9 or 10 ring atoms in which one 5-7 membered aromatic ring is fused to a second aromatic or non-aromatic ring. When the total number of S and O atoms in a heteroaryl group exceeds 1, the heteroatoms are not adjacent to each other. In one embodiment of the invention, the total number of S and O atoms in the heteroaryl group is not more than 2. In another embodiment of the invention, the total number of S and O atoms in

- 12 043505 aromatic heterocycle not more than 1. Examples of heteroaryl groups include, but are not limited to, pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazine yl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanil, benzofurazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, tetrahydrofuranyl and furopyridinyl. Heteroaryl groups are optionally independently substituted with one or more substituents described herein. Heteroaryloxy is a heteroaryl group as described linked to the group it replaces via an oxygen, -O-, linker.

Heterocycloalkyl is a saturated ring group. It may have, for example, 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, the remaining ring atoms being carbon. In a typical embodiment of the invention, nitrogen is a heteroatom. Monocyclic heterocycloalkyl groups typically have 3 to 8 ring atoms or 4 to 6 ring atoms. Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl and pyrrolinyl.

The term mono- and/or dialkylamino indicates secondary or tertiary alkylamino groups, where alkyl groups are independently selected alkyl groups as defined herein. The point of attachment of the alkylamino group is at nitrogen. Examples of mono- and dialkylamino groups include ethylamino, dimethylamino and methylpropylamino.

Dosage form means a unit of administration of the active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, solutions, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalation forms, transdermal forms, buccal forms, sublingual forms, topical forms, gel, mucosal forms and the like . The dosage form may also include an implant, for example an optical implant.

Pharmaceutical compositions are compositions containing 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 that may be combined in a single dosage form or provided together in separate dosage forms with instructions such that the active agents are used together to treat any disorder described herein.

Pharmaceutically acceptable salts include derivatives of the disclosed compounds in which the parent compound is modified by producing inorganic and organic, non-toxic acid or base addition salts. Salts of the compounds of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a corresponding base (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate and the like), or by reacting the free base forms of these compounds with a stoichiometric amount of an appropriate acids. Such reactions are typically carried out in water, or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are typical where practical. Salts of the compounds of the present invention further include solvates of the compounds and compound salts.

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

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

- 13 043505

Pharmaceutically acceptable excipient means an excipient that is suitable for the preparation of a pharmaceutical composition/combination that is generally safe, non-toxic and neither biologically nor otherwise suitable for administration to a host, and includes in one embodiment of the invention an excipient that is acceptable for use in veterinary medicine, as well as for pharmaceutical purposes for humans. A pharmaceutically acceptable excipient, as used herein, includes one or more such excipients.

The patient or host or subject is a human or non-human animal in need of modulation of the complement factor D pathway. As a rule, the owner is a person. Patient or host or subject also refers to, for example, mammals, primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.

A prodrug, as used herein, means a compound that, when administered to a host in vivo, is converted to the parent drug. As used herein, the term parent drug means any of the chemical compounds described herein that are useful for the treatment of any of the disorders described herein or for the control or amelioration of the underlying cause or symptoms associated with any physiological or pathological disorder described herein , the owner is usually human. Prodrugs can be used to achieve any desired effect, including improving the properties of the parent drug or improving the pharmaceutical or pharmacokinetic properties of the parent drug. The existence of a prodrug strategy provides choices in modulating the conditions for in vivo formation of the parent drug, all of which are considered to be included herein. Non-limiting examples of prodrug strategies include covalent attachment of removable groups or removable moieties of groups, such as, but not limited to, acylation, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxyl derivatives, sulfoxy or sulfonic derivatives, carbonylation or anhydride, among others.

Providing a compound of formula I with at least one additional active agent means a compound of formula I and the additional active agent(s) presented simultaneously in a single dosage form, presented in parallel in separate dosage forms, or presented in separate dosage forms for administration separated by some interval a time that is within the time that both the compound of Formula I and the at least one additional active agent are in the blood of the patient. In some embodiments of the invention, the compound of Formula I and the additional active agent do not have to be prescribed to the patient by the same health care professional. In some embodiments, the additional active agent or agents may not require a prescription. Administration of a compound of formula I or at least one additional active agent can occur by any suitable route, for example, oral tablets, oral capsules, oral solutions, inhalation, injection, suppository or local contact.

A therapeutically effective amount of a pharmaceutical composition/combination of the present invention means an amount effective when administered to a patient to provide a therapeutic benefit such as improvement of symptoms, for example, an amount effective to reduce symptoms of macular degeneration. In one embodiment of the invention, a therapeutically effective amount is an amount sufficient to prevent a significant increase or will significantly decrease the detectable level of complement factor D in the blood, serum or tissues of the patient.

II. Detailed description of active compounds.

The present invention provides a compound of formula I as well as pharmaceutically acceptable salts and compositions thereof. formula I can be considered to have a central core, a substituent LB and a substituent (C=O)A. It has been found that a compound of formula I, or a pharmaceutically acceptable salt or composition thereof, wherein R ¹² or R ¹³ on group A is aryl, heteroaryl or heterocycle, is an excellent inhibitor of complement factor D, and, therefore, can be used in an effective amount for treatment of a host requiring modulation of complement factor D.

Non-limiting examples of compounds falling within Formula I with variations in the variables, eg A, B, R1- ^R3 and L, are shown below. The description includes all combinations of these definitions resulting in stable compounds.

Formulas II-XXX.

In one aspect, the invention includes compounds and salts of formulas 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 XXX, which are within the scope of Formula I. The variables shown in Formulas IIXXX have the definitions set forth in the summary for Formula I or any definitions set forth herein. description.

- 15 043505

R ³ V

R ³ V

A

Formula XIV m is equal to 0 or 1.

Formula XV m is equal to 0 or 1.

Formula XVI

And A m is equal to 0 or 1. m is equal to 0 or 1.

Formula XVII

Formula XVIII m equals 0 or 1

Formula XIX

m is equal to 0 or 1.

Formula XX

Formula XXI

Formula XXII

m equals 0 or 1

Formula XXIII Formula XXIV Formula XXV

- 16 043505

In these embodiments, it is understood that where ^R1 or ^R3 is attached to a carbon atom, there may be two independent attachments, as in R2/ ^R2 , and these formulas should be considered to include all such variations.

In addition, the invention includes compounds and salts of formula I, and pharmaceutically acceptable compositions thereof, and any of their subformulas (II-XXX), in which at least one of the following conditions occurs in the embodiments of the invention described below.

Aryl, heteroaryl and heterocyclic substituents R ¹² and R ¹³ .

It has been surprisingly discovered that a compound of formula I, a pharmaceutically acceptable salt thereof, or a composition wherein R ¹² or R ¹³ on group A is aryl, heteroaryl or heterocycle, is an excellent inhibitor of complement factor D.

One of R ¹² and R ¹³ is selected from R ³¹ , and the other of R ¹² and R ¹³ is selected from R ³² . In another embodiment of the invention, each of R ¹² and R ¹³ can be independently selected from R ³² .

R ³¹ is selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, -COOH, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C6alkyl, -C0-C4alkyl(C3-C7cycloalkyl), C2-C6alkenyl, C2-C6alkanoyl, C1 -C6alkoxy, C2-C6alkenyloxy, -C(O)OR ⁹ , C1-C ₆ thioalkyl, -C ₀ -C ₄ alkyl-NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO2R ⁹ , -SO2NR ⁹ R ¹⁰ , -OC(O)R ⁹ and -C(NR ⁹ )NR ⁹ R ¹⁰ , each of R ³¹ which is other than hydrogen, halogen, hydroxyl, nitro, cyano, C1-C2haloalkyl and C1-C2haloalkoxy is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, -COOH, -CONH2, C1-C2haloalkyl and C1-C2haloalkoxy, and of which each R ³¹ is also optionally substituted with one substituent selected from phenyl and a 4-7 membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein the phenyl or 4-7-membered heterocycle is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C1-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkoxy, (mono- and di-C1C ₆ alkylamino) C ₀ -C ₄ alkyl, C ₁ -C ₆ alkyl ether, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C ₂ haloalkyl and C 1-C ₂ haloalkoxy;

R ³² is selected from aryl; a saturated or unsaturated heterocycle (for example, a 5-6 membered ring having 1, 2 or 3 heteroatoms independently selected from N, O and S), where the heterocycle is linked through a carbon atom in the heterocyclic ring to the carbon atom of ring A at the R ¹² position or R ¹³ ; and heteroaryl (for example, a 5-6 membered ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S), wherein the aryl, heterocycle or heteroaryl ring may be optionally substituted.

- 17 043505

Non-limiting examples of R ³² are

Non-limiting options R ¹² / R ¹³ .

In one embodiment of the invention, R ¹² is R ³² .

In one embodiment of the invention, R ¹³ is R ³² .

In one embodiment of the invention, R ¹² is R ³² , which is aryl.

In one embodiment of the invention, R ¹² is optionally substituted aryl.

In one embodiment of the invention, R ¹² is an optionally substituted saturated or unsaturated heterocycle linked through a carbon atom in the heterocyclic ring to the carbon atom of ring A at the R ¹² position.

In one embodiment of the invention, R ¹² is optionally substituted heteroaryl.

In one embodiment of the invention, R ¹³ is optionally substituted aryl.

In one embodiment of the invention, R ¹³ is an optionally substituted saturated or unsaturated heterocycle linked through a carbon atom in the heterocyclic ring to

- 18 043505 by the carbon atom of ring A at position R ¹³ .

In one embodiment of the invention, R ¹³ is optionally substituted heteroaryl.

In one embodiment of the invention, R ¹² is R ³² which is a (5- or 6-membered unsaturated or aromatic heterocycle) having 1, 2 or 3 heteroatoms independently selected from N, O and S, where (5- or A 6-membered unsaturated heterocycle) is attached via a carbon atom to the carbon atom CR ¹² or CR ¹³ .

In one embodiment of the invention, R ¹² is R ³² which is a (4-7 membered heterocycloalkyl) having 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein (4-7 membered heterocycloalkyl) is attached via carbon atom to carbon atom CR ¹² or CR ¹³ .

In one embodiment of the invention, R ¹³ is R ³² , which is aryl.

In one embodiment of the invention, R ¹³ is R ³² , which is a (5- or 6-membered unsaturated or aromatic heterocycle) having 1, 2 or 3 heteroatoms independently selected from N, O and S, where (5- or A 6-membered unsaturated heterocycle) is attached via a carbon atom to the carbon atom CR ¹² or CR ¹³ .

In one embodiment of the invention, R ¹³ is R ³² which (4-7 membered heterocycloalkyl) has 1, 2 or 3 heteroatoms independently selected from N, O and S, where (4-7 membered heterocycloalkyl) is bonded via a carbon atom to carbon CR ¹² or CR ¹³ .

In one embodiment, the invention relates to compounds of formula I, wherein one of R ¹² and R ¹³ is H and the other of R ¹² and R ¹³ is R ³² , where

R ³² is selected from aryl, which may be optionally substituted; (5- or 6-membered unsaturated or aromatic heterocycle) having 1, 2 or 3 heteroatoms independently selected from N, O and S, where (5- or 6-membered unsaturated heterocycle) is attached via a carbon atom to the CR ¹² carbon or CR ¹³ where (5- or 6-membered unsaturated or aromatic heterocycle) may be optionally substituted; and (4-7 membered heterocycloalkyl) having 1, 2 or 3 heteroatoms independently selected from N, O and S, where (4-7 membered heterocycloalkyl) is attached via a carbon atom to a CR ¹² or CR ¹³ carbon atom, and (4-7 membered heterocycloalkyl) may be optionally substituted.

In another embodiment, the invention relates to compounds of formula I, where

R ¹ , R ¹ , R ² and R ³ are all hydrogen;

R ² is fluorine and R ³ is hydrogen, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl) or -O-Co-C 4 alkyl (C ₃ -C ₇ cycloalkyl);

R ⁵ represents hydrogen, halogen or C ₁ -C ₂ αlkyl;

R ¹¹ , R ¹³ , R ¹⁴ and R ¹⁵ , if present, are independently selected in each case from hydrogen, halogen, hydroxyl, amino, C 1 -C ₄ alkyl, C 1 -C ₄ alkoxy, -C ₀ -C ₂ alkyl (mono - and di-C ₁ -C ₂ alkylamino), trifluoromethyl and trifluoromethoxy;

X ¹² represents CR ¹² ; And

R ¹² is selected from aryl, which may be optionally substituted; (5- or 6-membered unsaturated or aromatic heterocycle) having 1, 2 or 3 heteroatoms independently selected from N, O and S, where (5- or 6-membered unsaturated heterocycle) is attached via a carbon atom to the CR ¹² carbon or CR ¹³ where (5- or 6-membered unsaturated or aromatic heterocycle) may be optionally substituted; and (4-7 membered heterocycloalkyl) having 1, 2 or 3 heteroatoms independently selected from N, O and S, where (4-7 membered heterocycloalkyl) is attached via a carbon atom to a CR ¹² or CR ¹³ carbon atom, and (4-7 membered heterocycloalkyl) may be optionally substituted.

In one embodiment, the invention relates to compounds of formula I, where m is 0 or 1;

R ² is halogen, R ² ' is hydrogen or halogen, and R ³ is hydrogen, halogen, -C ₀ -C ₄ alkyl(C ₃ -C ₇ cycloalkyl) or -O-C ₀ -C ₄ alkyl( C ₃ -C ₇ cycloalkyl);

R ⁶ represents -C(O)C1-C ₄ alkyl, -C(O)NH ₂ , -C(O)CF ₃ , -C(O)(C ₃ -C ₇ cycloalkyl) or -ethyl(cyanoimino) ;

one of R ¹² and R ¹³ is selected from hydrogen, halogen, C1- _C4 alkyl, C1- _C4 alkoxy, trifluoromethyl and trifluoromethoxy; and the other of R ¹² and R ¹³ is R ³² where

R ³² is selected from aryl; a saturated or unsaturated heterocycle (for example, a 5-6 membered ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S), wherein the heterocycle is linked through a carbon atom in the heterocyclic ring to the carbon atom of ring A at the R ¹² position or R ¹³ ; and heteroaryl (eg, a 5-6 membered ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S), wherein the aryl, heterocycle or heteroaryl ring may be optionally substituted.

In one embodiment, the invention relates to compounds of formula I, wherein one of R ¹² and R ¹³ represents hydrogen, hydroxyl, halogen, methyl or methoxy; and the other of R ¹² and R ¹³ is R ³² where

R ³² is selected from aryl, heteroaryl or heterocycle linked to ring A through the carbon atom he-

- 19 043505 terocycle.

In one embodiment of the invention, R ³² may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH)2, -Si(CH3)3, -COOH, - CONH2, -P(O)(OH)2, ^^alkyl, ^^alkoxy, -C0-C2alkyl(mono- and di-C _g C ₄ alkylamino), C ₁ -C ₆ alkyl ether, C1-C ₄ alkylamino, C1- _C4 hydroxyalkyl, _C1 - _C2 haloalkyl and _C1 - _C2 haloalkoxy.

Remnant of the central core.

The remainder of the central core in formula I is shown below:

Remainder , | ^Ch _X 7 /

Central^-^: _o -_ /

Cores; X; _; >=O

And where Q ¹ represents N(R ¹ ) or C(R1R1);

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

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

X ¹ and X ² independently represent H, CH or CZ, or X ¹ and X ² together represent C=C; and where Q1, Q2, Q3, X1 and X2 are selected in such a way that stable compounds are obtained.

Non-limiting examples of the ring are shown below (any of which may be otherwise substituted with R1, R1', R2, R2', R3 and R3'), as described in more detail below.

where q is 0, 1, 2 or 3, and r is 1, 2 or 3.

R and R' are independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl, where each group may be optionally substituted, or any other substituent group herein that provides the desired properties. In some embodiments of the invention, the ring contains one or more chiral carbon atoms. The invention includes embodiments in which the chiral carbon may be present as an enantiomer or mixtures of enantiomers, including a racemic mixture. There,

- 20 043505 where the ring includes more than one stereocenter, all enantiomers and diastereomers are included in the invention as individual examples.

Z is F, Cl, NH2, _CH3 , CH2D, CHD2 or _CD3 .

R ¹ , R ¹ , R ² , R ² , R ³ and R ³ are independently selected in each case depending on the circumstances and only when stable compounds are obtained from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6αalkoxy, C2-C6alkynyl, C2-C6alkanoyl, C1-C6thioalkyl, hydroxyC1-C6alkyl, aminoC1-C6alkyl, -C0-C4alkyl-NR ⁹ R ¹⁰ , -C(O)OR ⁹ , -OC(O)R ⁹ , -NR ⁹ C(O)R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ , -NR ⁹ C(O)OR ¹⁰ , C1-C2haloalkyl and ^^haloalkoxy, where ^R9 and ^R10 are independently selected in each case from hydrogen, C1-C6αalkyl, ( _C3 -C7cycloalkyl) _C0C4alkyl , _{-C0 - C4alkyl} ( _C3 -C7cycloalkyl ) and -O-C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl).

Unlimited central core options.

In alternative embodiments of the invention, R ¹ and R ¹ or R ³ and R ³ can be taken together to form a 3-6 membered carbocyclic spiro ring or a 3-6 membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N , O or S; R ² and R ² can be taken together to form a 3-6 membered carbocyclic spiro ring; or R ² and R ² can be taken together to form a 3-6 membered heterocyclic spiro ring;

each of the rings may be unsubstituted or substituted with 1 or more substituents independently selected from halogen (and in particular F), hydroxyl, cyano, -COOH, C ₁ -C ₄ alkyl (including, in particular, methyl), C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C 1 -C ₄ alkoxy, C _{2 -C 4} alkanoyl, hydroxyC ₁ -C ₄ alkyl, (mono- and di-C ₁ -C ₄ alkylamino)C ₀ -C ₄ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -O -C ₀ -C ₄ alkyl (C ₃ C ₇ cycloalkyl), C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

In alternative embodiments of the invention, R ¹ and R ² can be taken together to form a 3-membered carbocyclic ring; R ¹ and R ² can be taken together to form a 4-6 membered carbocyclic or aryl ring or a 4-6 membered heterocyclic or heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, O and S; or R ² and R ³ , when bonded to adjacent carbon atoms, can be taken together to form a 3-6 membered carbocyclic or aryl ring or a 3-6 membered heterocyclic or heteroaryl ring;

each ring may be unsubstituted or substituted with 1 or more substituents independently selected from halogen (especially F), hydroxyl, cyano, -COOH, C ₁ -C ₄ alkyl (including, in particular, methyl), C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ αlkoxy, C ₂ -C ₄ alkanoia, hydroxyC ₁ -C ₄ alkyl, (mono di-C ₁ -C ₄ alkylamino)C ₀ -C ₄ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -O -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

In one embodiment of the invention, the central core residue is proline.

In one embodiment of the invention, the central core residue is 4fluoroproline.

In one embodiment of the invention, R ¹ , R ¹ , R ² , R ³ and R ³ , if present, are all hydrogen; and R ² is fluorine.

In one embodiment of the invention, R ¹ , R ¹ , R ² and R ³ , if present, are all hydrogen; and R ² is fluorine and R ³ is -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl) or -O -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl).

In one embodiment of the invention, R ¹ and R ² taken together form a 3-6 membered cycloalkyl group, and R ¹ , R ² , R ³ and R ³ , where present, are all hydrogen.

In one embodiment of the invention, R ¹ , R ¹ , R ³ and R ³ , if present, are all hydrogen, and R ² and R ² taken together form a 5- or 6-membered heterocycloalkyl group having 1 or 2 atoms oxygen.

In one embodiment of the invention, R ¹ represents hydrogen and R ² represents fluorine.

In one embodiment of the invention, 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 a substituted vinyl, for example:

- 21 043505

In one embodiment of the invention, the compound of formula I has the structure:

In one embodiment of the invention, the central pyrrolidine is modified by the addition of a second heteroatom to the pyrrolidine ring, such as N, O, S or Si, for example:

Another modification within the scope of the invention is the addition of a substituent to the central ring of the pyrrolidine in R ⁷ or R 8 to form a 5- or 6-membered heterocyclic ring, for example:

Examples of compounds having the modifications described above include:

Substituents L-B of the central core.

The L-B substituents of the central core in Formula I are given below:

from the formulas:

selected

L represents a bond or

is hydrogen, C ₁ -C ₆ alkyl or -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl) and R ^{18 0} ' where R ¹⁷ is and R ¹⁸ are independently selected from hydrogen, halogen, hydroxymethyl and methyl; and m is 0, 1, 2 or 3.

B is monocyclic or bicyclic carbocyclic; a monocyclic or bicyclic carbocyclic hydroxy 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 in the ring; C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl; -(C ₀ -C ₄ -alkyl)(aryl); -(C ₀ -C ₄ -alkyl)(heteroaryl); or -(C ₀ -C ₄ -alkyl)(biphenyl).

Each of B is unsubstituted or substituted with one or more substituents independently selected from R ³³ and R ³⁴ , as well as 0 or 1 substituents selected from R ³⁵ and R ³⁶ :

R ³³ is independently selected from halogen, hydroxyl, -COOH, cyano, €1-C6alkyl, C2-C6alkanoyl, €1-C6alkoxy, -C0-C4alkyl-NR ⁹ R ¹⁰ , -SO2R ⁹ , C1-C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy;

R ³⁴ is independently selected from nitro, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ thioalkyl, -JC3-C7Cycloalkyl, -B(OH)2, -JC(O)NR ⁹ R ²³ , -JOSO2OR ²¹ , -C(O)(CH2)i-4S(O)R ²¹ , -O(CH2)i-4S(O)NR ²¹ R ²² , -JOP(O)(OR ²¹ )(OR ²² ) , -JP(O)(OR ²¹ )(OR ²² ), -JOP(O)(OR ²¹ )R ²² , JP(O)(OR ²¹ )R ²² , -JOP(O)R ²¹ R ²² , -JP (O)R ²¹ R ²² , -JSP(O)(OR ²¹ )(OR ²² ), -JSP(O)(OR ²¹ )(R ²² ), -JSP(O)(R ²¹ )(R ²² ), -JNR ⁹ P(O)(NHR ²¹ )(NHR ²² ),

- 22 043505

-JNR ⁹ P(O)(OR ²¹ )(NHR ²² ), NR ⁹ P(O)(OR ²¹ )(OR ²² ), -JC(S)R ²¹ , -JNR ²¹ SO2R ²² , -JNR ⁹ S( O)NR ¹⁰ R ²² , -JNR ⁹ SO2NR ¹⁰ R ²² , -JSO2NR9COR ²² , -JSO2NR ⁹ CONR ²¹ R ²² , -JNR ²¹ SO2R ²² , -JC(O)NR ²¹ SO2R ²² , -JC(NH2)NR ²² , -JC(NH2)NR ⁹ S(O)2R ²² , -JOC(O)NR ²¹ R ²² , -JNR ²¹ C(O)OR ²² , -JNR ²¹ OC(O)R ²² , -(CH2)1 -4C(O)NR ²¹ R ²² , -JC(O)R ²⁴ R ²⁵ , -JNR ⁹ C(O)R ²¹ , -JC(O)R ²¹ , -JNR ⁹ C(O)NR ¹⁰ R ²² , -CCR ²¹ , -(CH2) _1-4 OC(O)R ²¹ and -JC(O)OR ²³ ; each of R ³⁴ may be unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH) ₂ , -Si(CH ₃ ) ₃ , -COOH, -CONH2, -P(O)(OH) ₂ , C ₁ -C ₆ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C ₆ alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C1- _C4 alkylamino), _C1 - _C6 alkyl ether, C1- _C4 alkylamino, C1- _C4 hydroxyalkyl, _C1 - _C2 haloalkyl and _C1 - _C2 haloalkoxy;

R ³⁵ is independently selected from naphthyl, naphthyloxy, indanyl, (4-7 membered heterocycloalkyl)C0C4alkyl containing 1 or 2 heteroatoms selected from N, O and S, and a bicyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and containing from 4 to 7 ring atoms in each ring; each of R ³⁵ is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C1- _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkanoyl, _C1 - _C6 alkoxy, (mono- and di-C ₁ -C ₆ alkylamino)C ₀ -C ₄ alkyl, C ₁ -C ₆ alkyl ether, -C ₀ -C ₄ alkyl (C ₃ C ₇ cycloalkyl), -SO2R ⁹ , C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy; And

R ³⁶ is independently selected from tetrazolyl, (phenyl)C0-C2alkyl, (phenyl)C1-C2alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, B and S, each of R ³⁶ is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C1- _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkanoyl, _C1 - _C6 alkoxy, (mono- and di-C1C ₆ alkylamino) C ₀ -C ₄ alkyl, C ₁ -C ₆ alkyl ether, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -SO2R ⁹ ,

-OSi(CH ₃ ) ₂ C(CH ₃ ) ₃ , -Si(CH ₃ ) ₂ C(CH ₃ ) ₃ , C ₁ -C ₂ haloalkyl and C _1-2 haloalkoxy.

J is independently selected in each case from a covalent bond, C1- _C4 alkylene, _-OC1 - _C4 alkylene, _C2 - _C4 alkenylene, and _C2 - _C4 alkynylene.

In one embodiment of the invention -L-B- is

R ²⁶ and R ²⁷ are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkyl, -C ₀ -C ₄ alkyl (mono- and di-C1C ₆ alkylamino), -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -C ₀ -C ₄ alkoxy (C ₃ -C ₇ cycloalkyl), C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy and C ₁ -C ₂ haloalkylthio.

Unlimited L-B options.

In another embodiment of the invention -L-B- is

R ¹⁸ and R ¹⁸ are independently selected from hydrogen, halogen, hydroxymethyl and methyl; and m is 0 or 1; And

R ²⁶ , R ²⁷ and R ²⁸ are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, C1-C6thioalkyl, (mono- and di-C1-C6alkylamino )C0C4alkyl, (C3-C7cycloalkyl)C0-C4alkyl, (aryl)C0-C4alkyl-, (heteroaryl)C0-C4alkyl- and -C0-C4alkoxy(C3-C7cycloalkyl); each of which R ²⁶ , R ²⁷ , R ²⁸ , other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, C 1 -C ₂ alkoxy, C ₁ -C ₂ haloalkyl,

- 23 043505 (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl and C1-C2 haloalkoxy; And

R ²⁹ represents hydrogen, C1-C ₂ alkyl, C1-C ₂ haloalkyl or Si(CH ₃ ) ₂ C(CH ₃ ) ₃ .

In one embodiment of the invention, m is 0.

In one embodiment, the invention further includes compounds and salts of formula I, wherein B represents 2-fluoro-3-chlorophenyl. In another embodiment of the invention, another carbocyclic, aryl, heterocyclic or heteroaryl group is used, such as 2bromo-pyridin-6-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl, 2,2- dichlorocyclopropylmethyl or 2-fluoro-3trimethylsilylphenyl.

In another embodiment, B is phenyl, pyridyl or indanyl, each of which is unsubstituted or substituted with one or more substituents independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkyl, (mono- and di-C1-C ₆ alkylamino)C ₀ -C ₄ alkyl, (C ₃ -C7cycloalkyl)C ₀ C ₄ alkyl, -C ₀ -C ₄ alkoxy (C ₃ -C ₇ cycloalkyl), (phenyl)C ₀ -C ₂ alkyl, (pyridyl)C ₀ -C ₂ alkyl; each of the substituents other than hydrogen, halogen, hydroxyl, nitro, cyano is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxyl, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, -OSi (CH ₃ ) ₂ C(CH ₃ ) ₃ , -Si(CH ₃ ) ₂ C(CH ₃ ) ₃ , C ₁ -C ₂ haloalkyl and C1-C2haloalkoxy.

In another embodiment, B is phenyl or pyridyl substituted with 1, 2 or 3 substituents selected from chlorine, bromine, hydroxyl, -SCF3, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, trifluoromethyl, phenyl and trifluoromethoxy , each of the substituents other than chlorine, bromine, hydroxyl, -SCF ₃ may be optionally substituted.

In some embodiments, B is a 2-fluoro-3-chlorophenyl or 2-fluoro-3-trifluoromethoxyphenyl group.

In one embodiment of the invention, B is pyridyl, optionally substituted with halogen, C ₁ -C ₂ alkoxy and trifluoromethyl.

In one embodiment of the invention, B is phenyl substituted with 1, 2 or 3 substituents independently selected from halogen, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, trifluoromethyl and optionally substituted phenyl.

In one embodiment of the invention, R ²³ is independently selected in each case from (C ₃ -C 7 -cycloalkyl)C ₀ -C ₄ -alkyl, (phenyl)C ₀ -C ₄ -alkyl, (4-7-membered heterocycloalkyl)C ₀ -C ₄ alkyl having 1, 2 or 3 heteroatoms, independently selected from N, O and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C ₀ -C ₄ alkyl having 1, 2, or 3 heteroatoms, independently selected from N, O and S.

In one embodiment of the invention, B is selected from

- 24 043505

- 25 043505

- 26 043505

- 27 043505

- 28 043505

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

Substituent (C=O)A of the central nucleus.

The (C=O)A substituent of the central core in Formula I is shown below:

- 29 043505

A represents a group selected from:

R ⁴ is selected from -CHO, -CONH2, C2-C6alkanoyl, hydrogen, -SO2NH2, -C(CH ₂ ) ₂ F, -CH(CF3)NH2, C1C ₆ alkyl, -C ₀ -C ₄ alkyl (C ₃ - C ₇ cycloalkyl), -C(O)C ₀ -C ₂ alkyl (C ₃ -C ₇ cycloalkyl),

each of R ⁴ other than hydrogen, -CHO and -CONH2 is unsubstituted or substituted by one or more of amino, imino, halogen, hydroxyl, cyano, cyanoimino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, - C ₀ -C ₂ alkyl (mono- and di-C1-C ₄ alkylamino), C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

R ⁵ and R ⁶ are independently selected from -CHO, -C(O)NH2, -C(O)NH(CH3), C2-C6alkanoia, hydrogen, hydroxyl, halogen, cyano, nitro, -COOH, -SO2NH2, vinyl, C1-C6alkyl (including methyl), C2-C6alkenyl, C1-C6alkoxy, -C0-C4alkyl(C3-C7cycloalkyl), -C(O)C0-C4alkyl(C3-C7cycloalkyl), -P(O)(OR ⁹ )2 , OC(O)R ⁹ , -C(O)OR ⁹ , -C(O)N(CH ₂ CH ₂ R ⁹ )(R ¹⁰ ), -NR ⁹ C(O)R ¹⁰ , phenyl or 5- or 6-membered heteroaryl.

Each R ⁵ and R ⁶ other than hydrogen, hydroxyl, cyano, and -COOH is unsubstituted or optionally substituted. For example, R ⁵ and R ⁶ other than hydrogen, hydroxyl, cyano and -COOH may be substituted with one or more substituents independently selected from halogen, hydroxyl, amino, imino, cyano, cyanoimino, C ₁ -C ₂ alkyl, C1 -C ₄ alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C1C ₄ alkylamino), C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

R ⁶ is hydrogen, halogen, hydroxyl, C1- _C4 alkyl, _-C0 - _C4 alkyl ( _C3 - _C7 cycloalkyl) or C1- _C4 alkoxy; or R ⁶ and R ⁶ can be taken together to form an oxo, vinyl or imino group.

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

- 30 043505

R ⁸ and R ⁸ are independently selected from hydrogen, halogen, hydroxyl, C1- _C6 alkyl, _-C0 - _C4 alkyl( _C3C7 cycloalkyl), _C1 - _C6 alkoxy and (C1- _C4 alkylamino) _{C 0} -C2alkyl; or R ⁸ and R ⁸ taken together form an oxo group; or R ⁸ and R ⁸ can be taken together with the carbon atom to which they are bonded to form a 3-membered carbocyclic ring.

R ¹⁶ is absent or may include one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ alkyl, C 2 -C ₆ alkenyl, C 2 -C ₆ alkanoyl, C ₁ -C ₆ alkoxy, -C _o C ₄ alkyl (mono- and di-C1-C ₆ alkylamino), -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C ₂ haloalkyl and C ₁ C ₂ haloalkoxy.

R ¹⁹ represents hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, -SO2C1-C6alkyl, (mono-di-C1-C6alkylamino)C1-C4alkyl, -C0-C4alkyl(C3-C7cycloalkyl), -C0-C4alkyl( C3-C7heterocycloalkyl), -C0-C4alkyl(aryl), C0-C4alkyl(heteroaryl), and where R ¹⁹ other than hydrogen is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxyl, amino, -COOH and -C(O)OC1-C ₄ alkyl.

X ¹¹ represents N or CR ¹¹ .

X ¹² represents N or CR ¹² .

X ¹³ represents N or CR ¹³ .

X ¹⁴ represents N or CR ¹⁴ .

At most 2 of ^X11 , ^X12 , ^X13 and ^X14 are N.

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

In one embodiment of the invention, R ⁵ and R ⁶ are independently selected from -CHO, -C(O)NH ₂ , -C(O)NH(CH ₃ ), C ₂ -C ₆ alkanoyl and hydrogen.

In one embodiment of the invention, each of R ⁵ and R ⁶ other than hydrogen, hydroxyl, cyano and -COOH is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, imino, cyano, cyanoimino, C ₁ -C ₂ alkyl, C ₁ C ₄ alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C ₁ -C ₄ alkylamino), C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

In one embodiment of the invention, R ⁸ and R ⁸ independently represent hydrogen or methyl.

In one embodiment of the invention, R ⁸ and R ⁸ are hydrogen.

In one embodiment of the invention, R ⁷ is hydrogen or methyl.

In one embodiment of the invention, R ⁷ is hydrogen.

Formula options IA, IB, IC and ID.

To further illustrate the invention, various embodiments of formulas IA, IB, IC and ID are disclosed. They are presented by way of example to show some of the variations among the present compounds within the scope of the invention, and can be applied to any of Formulas I-XXX.

In one aspect, the present disclosure includes compounds and salts of formula IA:

R ⁶ , R ¹³ and B may have any of the definitions set forth herein for this variable.

In another aspect, the present disclosure includes compounds and salts of formulas IB, IC and ID.

In formulas IA, IB, IC and ID, the variables may include any of the definitions set forth herein that results in a stable connection. In some embodiments

- 31 043505 of the invention the following conditions apply for formulas IB and IC.

In some embodiments of the invention, structures are provided that include the formulas

IB and IC, where m=0, R ¹ is H, R ² is F, R ⁶ is alkanoyl, R ¹² is R ³² , R ³² is heteroaryl, R ¹³ is H and B is heteroaryl .

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=0, R ¹ and R ² are joined to form a 3-membered ring, R ⁶ is alkanoyl, R ¹² is R ³² , R ³² is heteroaryl , R ¹³ represents H and B represents heteroaryl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=0, R ¹ is H, R ² is F, R ⁶ is amide, R ¹² is R ³² , R ³² is heteroaryl, R ¹³ represents H and B represents heteroaryl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=0, R ¹ and R ² are joined to form a 3-membered ring, R ⁶ is an amide, R ¹² is R ³² , R ³² is a heteroaryl , R ¹³ represents H and B represents heteroaryl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=0, R ¹ is H, R ² is F, R ⁶ is alkanoyl, R ¹² is H, R ¹³ is R ³² , R ³² represents heteroaryl and B represents heteroaryl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=0, R ¹ and R ² are joined to form a 3-membered ring, R ⁶ is alkanoyl, R ¹² is H, R ¹³ is R ³² , R ³² represents heteroaryl and B represents heteroaryl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=0, R ¹ is H, R ² is F, R ⁶ is an amide, R ¹² is H, R ¹³ is R ³² . R ³² represents heteroaryl and B represents heteroaryl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=0, R ¹ and R ² are joined to form a 3-membered ring, R ⁶ is an amide, R ¹² is H, R ¹³ is R ³² , R ³² represents heteroaryl and B represents heteroaryl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=0, R ¹ is H, R ² is F, R ⁶ is alkanoyl, R ¹² is R ³² , R ³² is heteroaryl, R ¹³ represents H and B represents phenyl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=0, R ¹ and R ² are joined to form a 3-membered ring, R ⁶ is alkanoyl, R ¹² is R ³² , R ³² is heteroaryl , R ¹³ represents H and B represents phenyl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=0, R ¹ is H, R ² is F, R6 is amide, R ¹² is R ³² , R ³² is heteroaryl, R ¹³ represents H and B represents phenyl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=0, R ¹ and R ² are joined to form a 3-membered ring, R ⁶ is an amide, R ¹² is R ³² , R ³² is a heteroaryl , R ¹³ represents H and B represents phenyl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=0, R ¹ is H, R ² is F, R ⁶ is alkanoyl, R ¹² is H, R ¹³ is R ³² , R ³² represents heteroaryl and B represents phenyl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=0, R ¹ and R ² are joined to form a 3-membered ring, R ⁶ is alkanoyl, R ¹² is H, R ¹³ is R ³² , R ³² represents heteroaryl and B represents phenyl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=0, R ¹ is H, R ² is F, R ⁶ is an amide, R ¹² is H, R ¹³ is R ³² . R ³² represents heteroaryl and B represents phenyl.

In some embodiments of the invention, structures are provided that include the formulas

- 32 043505

IB and IC, where m=0, R ¹ and R ² are connected to form a 3-membered ring, R ⁶ is an amide, R ¹² is H, R ¹³ is R ³² , R ³² is heteroaryl and B is phenyl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=1, R ¹ is H, R ² is F, R ⁶ is alkanoyl, R ¹² is R ³² , R ³² is heteroaryl, R ¹³ represents H and B represents heteroaryl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=1, R ¹ and R ² are joined to form a 3-membered ring, R ⁶ is alkanoyl, R ¹² is R ³² , R ³² is heteroaryl , R ¹³ represents H and B represents heteroaryl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=1, R ¹ is H, R ² is F, R ⁶ is amide, R ¹² is R ³² , R ³² is heteroaryl, R ¹³ represents H and B represents heteroaryl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=1, R ¹ and R ² are joined to form a 3-membered ring, R ⁶ is an amide, R ¹² is R ³² , R ³² is a heteroaryl , R ¹³ represents H and B represents heteroaryl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=1, R ¹ is H, R ² is F, R ⁶ is alkanoyl, R ¹² is H, R ¹³ is R ³² , R ³² represents heteroaryl and B represents heteroaryl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=1, R ¹ and R ² are joined to form a 3-membered ring, R ⁶ is alkanoyl, R ¹² is H, R ¹³ is R ³² , R ³² represents heteroaryl and B represents heteroaryl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=1, R ¹ is H, R ² is F, R ⁶ is an amide, R ¹² is H, R ¹³ is R ³² . R ³² represents heteroaryl and B represents heteroaryl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=1, R ¹ and R ² are joined to form a 3-membered ring, R ⁶ is an amide, R ¹² is H, R ¹³ is R ³² , R ³² represents heteroaryl and B represents heteroaryl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=1, R ¹ is H, R ² is F, R ⁶ is alkanoyl, R ¹² is R ³² , R ³² is heteroaryl, R ¹³ represents H and B represents phenyl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=1, R ¹ and R ² are joined to form a 3-membered ring, R ⁶ is alkanoyl, R ¹² is R ³² , R ³² is heteroaryl , R ¹³ represents H and B represents phenyl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=1, R ¹ is H, R ² is F, R ⁶ is amide, R ¹² is R ³² , R ³² is heteroaryl, R ¹³ represents H and B represents phenyl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=1, R ¹ and R ² are joined to form a 3-membered ring, R ⁶ is an amide, R ¹² is R ³² , R ³² is a heteroaryl , R ¹³ represents H and B represents phenyl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=1, R ¹ is H, R ² is F, R ⁶ is alkanoyl, R ¹² is H, R ¹³ is R ³² , R ³² represents heteroaryl and B represents phenyl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=1, R ¹ and R ² are joined to form a 3-membered ring, R ⁶ is alkanoyl, R ¹² is H, R ¹³ is R ³² , R ³² represents heteroaryl and B represents phenyl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m=1, R ¹ is H, R ² is F, R ⁶ is an amide, R ¹² is H, R ¹³ is R ³² . R ³² represents heteroaryl and B represents

- 33 043505 is phenyl.

In some embodiments of the invention, structures are provided that include the formulas

IB and IC, where m=1, R ¹ and R ² are connected to form a 3-membered ring, R ⁶ is an amide, R ¹² is H, R ¹³ is R ³² , R ³² is heteroaryl and B is phenyl.

Variants of formula VII.

To further illustrate the invention, various variations of Formula VII are provided. In one aspect, the disclosure includes compounds and salts of Formula VII:

R ¹ , R ² , R ² and R ³ are independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, -C0-C2 alkylNR9R ¹⁰ , -C0-C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -O- C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C ₂ haloalkyl and C ₁ C ₂ haloalkoxy;

R8 and R8 are independently selected from hydrogen, halogen and methyl;

R ⁵ represents hydrogen, hydroxyl, cyano, -COOH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ C ₆ alkanoyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), - C(O)C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C ₂ haloalkyl or C ₁ -C ₂ haloalkoxy;

R ⁶ is -C(O)CH ₃ , -C(O)NH ₂ , -C(O)CF ₃ , -C(O)(cyclopropyl) or -ethyl(cyanoimino); And

R ¹¹ and R ¹⁴ are independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkyl, -C ₀ -C ₄ alkyl (mono- and di-C1C ₆ alkylamino), -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -OC ₀ -C ₄ alkyl (C ₃ - C ₇ cycloalkyl), C ₁ -C ₂ haloalkyl and C 1 -C ₂ haloalkoxy.

Prodrugs of Formula I are also included within the scope of this disclosure.

Pharmaceuticals.

The compounds described herein may be administered as a pure chemical, but may also be administered as a pharmaceutical composition that includes an effective amount for the host in need of treatment of a selected compound of Formula I as described herein. Accordingly, the invention relates to pharmaceutical compositions containing an effective amount of a 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 sole active agent or, in an alternative embodiment of the invention, formula I and at least one additional active agent. In some embodiments, the pharmaceutical composition is in a dosage form containing from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg 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 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 substance or a salt thereof. The pharmaceutical composition may also include a molar ratio of a compound of formula I and an additional active agent. For example, the pharmaceutical composition may contain a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1, or about 1.5:1 to about 4:1 of the other anti-inflammatory agent.

The compounds disclosed herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, by implant, including ophthalmic implant, transdermally, buccally, rectally, as an ophthalmic solution, by injection, including ophthalmic injection, intravenous, intra-aortic, intracranial or other means in dosage unit forms containing conventional pharmaceutically acceptable carriers. The pharmaceutical composition may be formulated in any pharmaceutically acceptable form, for example, an aerosol, cream, gel, tablet, capsule, tablet, syrup, transdermal patch or ophthalmic solution. Some dosage forms, such as tablets and capsules, are divided into appropriately sized unit doses containing appropriate amounts of active ingredients, eg, 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 be suitable for administration to the patient being treated. The carrier may be inert or it may have its own pharmaceutical benefits. The amount of carrier used in combination with the compound is sufficient to provide a practical amount of material to be administered per unit dose of the compound.

Classes of carriers include, but are not limited to, binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tabletting 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 as a diluent in others. Examples of pharmaceutically acceptable carriers include sugars, starches, celluloses, tragacanth powder, maltose, gelatin; talc and vegetable oils. Optional active agents that do not substantially affect the activity of the compound of the present invention may be included in the pharmaceutical composition.

Pharmaceutical compositions/combinations can be formulated for oral administration. These compositions may contain any amount of the active compound of Formula I that achieves the desired result, for example, from 0.1 to 99% by weight (wt%) of the compound of Formula I, and typically at least about 5 wt% of the compound of Formula I. Some embodiments contain from about 25 to about 50% by weight, or from about 5 to about 75% by weight, of a 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, intraperitoneal, subcutaneous, transnasal, sublingual or rectal. Local administration for ocular administration includes: topical, intravitreal, periocular, transscleral, retrobulbar, periscleral, subepiscleral, or via an intraocular device. Inhibitors can be delivered by a delayed delivery device implanted intravitally or transscleralally, or by other known means of local delivery to the eye.

Methods of treatment.

The compounds and pharmaceutical compositions disclosed herein can be used to treat or prevent a disorder mediated by the complement pathway, and in particular a pathway that is modulated by complement factor D. In some embodiments, the disease is an inflammatory disease, an immune disease, an autoimmune disease, or a complement factor D-related disease in the host. In one embodiment of the invention, the disease is an ocular disease. Complement-mediated diseases that may be treated or prevented by the compounds and compositions of the present invention include, but are not limited to, the inflammatory effects of sepsis, systemic inflammatory response syndrome (SIRS), ischemia/reperfusion injury (I/R injury), psoriasis, myasthenia gravis , systemic lupus erythematosus (SLE), paroxysmal nocturnal hemoglobinuria (PNH), hereditary angioedema, multiple sclerosis, trauma, burns, 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 nephritis, Crohn's disease, rheumatoid arthritis, atherosclerosis, transplant rejection , prevention of fetal loss, biomaterial reactions (eg, hemodialysis, implants), C3 glomerulonephritis, abdominal aortic aneurysms, neuromyelitis optica (NMO), vasculitis, neurological disorders, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, diseases with inappropriate or unwanted activation complement, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2-induced toxicity during IL-2 therapy, inflammatory diseases, inflammatory autoimmune diseases, adult respiratory distress syndrome, thermal injury including burns or frostbite, myocarditis, post-ischemic reperfusion conditions, balloon angioplasty, post-hemodialysis syndrome in the cardiopulmonary or renal circulation, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, complex immune diseases and autoimmune diseases, SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, tissue regeneration and neuronal regeneration. In addition, other known complement-related diseases are lung diseases and disorders such as dyspnea, hemoptysis, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary emboli and infarctions, pneumonia, fibrogenic dust diseases, inert dusts and minerals (eg, silica). , coal dust, beryllium and asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (due to irritant gases and chemicals such as chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia and hydrochloric acid), smoke injury , thermal injury (eg, burn, frostbite), bronchospasm, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, pauci-immune vasculitis, immune complex-associated inflammation, uveitis

- 35 043505 (including Behçet's disease and other subtypes of uveitis), antiphospholipid syndrome, arthritis, autoimmune heart disease, inflammatory bowel disease, ischemia-reperfusion injury, Barraquer-Simons syndrome, hemodialysis, systemic lupus erythematosus, erythematous lupus erythematosus, transplantation, diseases of the central nervous system and other neurodegenerative conditions, glomerulonephritis (including proliferative membrane glomerulonephritis), blistering skin diseases (including bullous pemphigoid, pemphigus and epidermolysis bullosa), ocular cicatricial pemphigoid, MPGN II, uveitis, adult macular degeneration, diabetic retinopathy, retinitis pigmentosa, macular edema, Behçet's uveitis, multifocal choroiditis, Vogt-Koyanga-Harad syndrome, intermediate uveitis, shotgun retinochoroiditis, sympathetic ophthalmia, ocular dicatric pemphigoid, ocular pemphigus, ischemic optic neuropathy, postoperative inflammation and occlusion in en retina.

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

In one embodiment, the invention relates to a method of treating paroxysmal nocturnal hemoglobinuria (PNH), which includes administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method of treating age-related macular degeneration (AMD), which includes administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method of treating rheumatoid arthritis, which includes administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method of treating multiple sclerosis, which includes administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method of treating myasthenia gravis, which includes administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method of treating atypical hemolytic uremic syndrome (aHUS), which includes administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method of treating C3 glomerulonephritis, which includes administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method of treating an abdominal aortic aneurysm, which comprises administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method of treating neuromyelitis optica (NMO), which includes administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

In some embodiments, the present invention provides methods for treating or preventing an inflammatory or complement disorder by administering to a host in need thereof an effective amount of a compound of Formula I of the invention. In some embodiments, the present invention provides methods for treating or preventing an inflammatory disorder, more generally an immune disorder, an autoimmune disorder, or complement factor D-related diseases, by providing an effective amount of a compound or pharmaceutically acceptable salt of Formula I to a factor D-mediated patient. inflammatory disorder. The compound or salt of Formula I may be provided as the sole active agent or may be provided together with one or more additional active agents.

In one embodiment, the invention provides a method of treating a disorder associated with dysfunction in the complement cascade, which includes administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In one embodiment, the invention provides a method of inhibiting activation of the alternative complement pathway in a subject, which comprises administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In one embodiment, the invention provides a method of modulating factor D activity in a subject, which comprises administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

- 36 043505

Prevention, as used herein, means that the likelihood of symptoms occurring in a patient prophylactically administered the compound is reduced relative to the likelihood of symptoms occurring in patients not administered the compound, or the severity of symptoms in a patient prophylactically administered the compound is reduced. compared to the severity of symptoms experienced by patients with the disorder or condition who were not administered the compound. In an alternative embodiment of the invention, an effective amount of a compound of formula I is used to prevent or prevent disorders associated with complement factor D.

An effective amount of a pharmaceutical composition/combination of the invention may be an amount sufficient to (a) inhibit the progression of a complement-mediated disorder, including an inflammatory disorder, an immune disorder, including an autoimmune disorder, or a factor D-related disease; (b) initiating regression of an inflammatory, immune, including autoimmune, disorder or factor D-related disease; or (c) initiation of treatment for an inflammatory, immune, including autoimmune, disorder or factor D-related disease.

An effective amount of a compound or pharmaceutical composition described herein also provides a sufficient amount of active agent that, when administered to a patient, provides a clinical benefit. This amount can be determined experimentally, for example, by assessing the concentration of the agent in the blood, or theoretically, by calculating bioavailability.

Combination therapy.

In one embodiment of the invention, a compound or salt of Formula I may be presented in combination or in alternation with at least one additional complement inhibitor or a second active compound with a different biological mechanism of action. In one embodiment of the invention, a compound or salt of Formula I may be presented in combination with a C5 complement inhibitor or a C5 convertase inhibitor. In another embodiment of the invention, a compound or salt of Formula I may be presented in combination with eculizumab. In one embodiment of the invention, a compound or salt of Formula I may be presented in combination with additional factor D inhibitors.

In one embodiment of the invention, a compound or salt of Formula I may be presented together with a compound that inhibits an enzyme that metabolizes protease inhibitors. In one embodiment of the invention, a compound or salt of Formula I may be presented together with ritonavir.

In non-limiting embodiments of the invention, a compound or salt of Formula I may be provided together with a protease inhibitor, soluble complement regulator, therapeutic antibody (monoclonal or polyclonal), complement component inhibitors, receptor agonists, or siRNAs.

Non-limiting examples of active agents in these categories.

Protease inhibitors: plasma-derived C ₁ -INH concentrates, such as Cetor® (Sanquin), Berinert-P® (CSL Behring, Lev Pharma) and Cinryze®; and recombinant human C1 inhibitors, such as Rhucin®.

Soluble complement regulators: soluble complement receptor 1 (TP10) (Avant Immunotherapeutics); sCR1-sLe ^x /TP-20 (Avant Immunotherapeutics); MLN-2222/CAB-2 (Millenium Pharmaceuticals); Mirococept (Inflazyme Pharmaceuticals).

Therapeutic antibodies: eculizumab/Soliris (Alexion Pharmaceuticals); Pexelizumab (Alexion Pharmaceuticals); Ofatumumab (Genmab A/S); TNX-234 (Tanox); TNX-558 (Tanox); TA106 (Taligen Therapeutics); Neutrazumab (G2 Therapies); Anti-properdin (Novelmed Therapeutics); HuMax-CD38 (Genmab A/S).

Complement component inhibitors: Compstatin/POT-4 (Potentia Pharmaceuticals); ARC 1905 (Archemix).

Receptor agonists: PMX-53 (Peptech Ltd.); JPE-137 (Jerini); JSM-7717 (Jerini).

Others: recombinant human MBL (rhMBL; Enzon Pharmaceuticals).

In one embodiment, the present invention provides a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of a composition containing a compound of the present invention. In one embodiment, the compositions of the present invention are administered in combination with an anti-VEGF agent. Non-limiting examples of anti-VEGF agents include, but are not limited to, aflibercept (Eylea®; Regeneron Pharmaceuticals); ranibizumab (Lucentis®: Genentech and Novartis); and pegaptanib (Macugen®; OSI Pharmaceuticals and Pfizer); Bevacizumab (Avastin; Genentech/Roche); anecortane acetate, squalamine lactate and corticosteroids including, but not limited to, triamcinolone acetonide.

- 37 043505

In another embodiment of the invention, a compound of Formula I may be combined with a second agent for treating an ocular disorder.

Examples of the types of therapeutic agents that may be used in combination for ophthalmic applications include anti-inflammatory drugs, antimicrobial agents, anti-angiogenesis agents, immunosuppressants, antibodies, steroids, ophthalmic antihypertensive drugs, and combinations thereof. Examples of therapeutic agents include amikacin, anecortane acetate, anthracenedione, anthracycline, azole, amphotericin B, bevacizumab, camptothecin, cefuroxime, chloramphenicol, chlorhexidine, chlorhexidine digluconate, clotrimazole, clotrimazole cephalosporin, corticosteroids, dexamethasone, desamethasone, econazole, e phtazidime, epipodophyllotoxin, fluconazole, flucytosine, fluoropyrimidines, fluoroquinolines, gatifloxacin, glycopeptides, imidazoles, itraconazole, ivermectin, ketoconazole, levofloxacin, macrolides, miconazole, miconazole nitrate, moxifloxacin, natamycin, neomycin, nystatin, ofloxacin, polyhexamethylene biguanide, prednisolone, and prednisolone acetate, pegaptanib, platinum analogues, polymycin B, propamidine isethionate, pyrimidine nucleoside, ranibizumab, squalamine lactate, sulfonamides, triamcinolone, triamcinolone acetonide, triazoles, vancomycin, vascular endothelial growth factor (VEGF) inhibitory agents, VEGF antibodies, VEGF antibody fragments, vinca alkaloid, timolol, betaxolol, travoprost , latanoprost, bimatoprost, brimonidine, dorzolamide, acetazolamide, pilocarpine, ciprofloxacin, azithromycin, gentamicin, tobramycin, cefazolin, voriconazole, ganciclovir, sidofovir, foscarnet, diclofenac, nepafenac, ketorolac, ibuprofen, indomethacin, fluoromethalone, p imexolone, anecortave, cyclosporine, methotrexate , tacrolimus and combinations thereof. Examples of eye diseases that may be treated in accordance with the compositions and methods described herein include amoebic keratitis, fungal keratitis, bacterial keratitis, viral keratitis, onchocerciasis keratitis, bacterial keratoconjunctivitis, viral keratoconjunctivitis, corneal dystrophies, Fuchs' endothelial dystrophy , Sjogren's syndrome, Stevens-Johnson syndrome, autoimmune dry eye diseases, environmental dry eye diseases, neovascularization diseases of the cornea, treatment and prevention of corneal transplant rejection, autoimmune uveitis, infectious uveitis, anterior uveitis, posterior uveitis (including toxoplasmosis), panuveitis, inflammatory disease of the vitreous or retina, prevention and treatment of endophthalmitis, macular edema, macular degeneration, age-related macular degeneration, proliferative and non-proliferative diabetic retinopathy, hypertensive retinopathy, autoimmune retinal disease, primary and metastatic intraocular melanoma, other intraocular metastatic tumors, open-angle glaucoma, closed-angle glaucoma, pigmentary glaucoma and their combinations.

A compound of Formula I or a combination of Formula I and another active agent can be administered to the ocular section by injection into the vitreous chamber, subretinal space, subchoroidal space, episclera, conjunctiva, sclera, anterior chamber, and cornea, and sections therein (e.g., subepithelial , intrastromal, endothelial).

In an alternative embodiment of the invention, a compound of Formula I or a combination of Formula I and another active agent can be administered to the ocular section by binding to mucosal penetrating particles to treat a condition located in the vitreous chamber, subretinal space, subchoroidal space, episclera, conjunctiva, the sclera or anterior chamber, and the cornea, and sections therein (eg, subepithelial, intrastromal, endothelial). Mucosal penetrating particles are known in the art and are described, for example, in published PCT application WO 2013166436 Kala Pharmaceuticals, which is incorporated herein in its entirety.

In other embodiments, the invention provides a composition containing a compound of Formula I suitable for topical administration to the eye. The pharmaceutical composition contains a plurality of coated particles containing a core particle containing a compound of Formula I, wherein Formula I constitutes at least about 80 wt.% of the particle core and the coating contains one or more surface modifying agents, wherein one of the more surface modifying agents contains at least at least one poloxamer, poly(vinyl alcohol) or polysorbate. One or more surface altering agents are present on the outer surface of the particle core with a density of at least 0.01 molecules/nm. One or more surface altering agents are present in the pharmaceutical composition in an amount of from about 0.001 to about 5% by weight. Many of the coated particles have an average smallest cross-sectional size of less than about 1 micron. The pharmaceutical composition also includes one or more ophthalmologically acceptable carriers, additives and/or diluents.

Those skilled in the art will appreciate that particles suitable for use in the methods disclosed herein may exist in a variety of forms, including, but not limited to, spheroids, rods, disks, pyramids, cubes, cylinders, nanospirals, nanosprings, nanorings, rod-shaped particles, arrow-shaped particles, drop-shaped particles, tetrapod-shaped particles, prismatic particles and many other geometric and non-geometric shapes. In some embodiments, the particles described herein

- 38 043505 have a spherical shape.

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 containing a compound of the present 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 containing a compound of the present invention, in combination or in alternation with additional complement inhibitors or other active compound with a different biological mechanism of action. In another embodiment, the present invention provides a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of a composition containing a compound of the present invention, in combination or alternating with eculizumab.

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 containing a compound of the present 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 containing a compound of the present invention in combination or alternation with an additional complement inhibitor. 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 containing a compound of the present invention, in combination or alternating with methotrexate.

In some embodiments, a compound of formula I is administered in combination or alternation with at least one anti-rheumatoid arthritis drug selected from: salicylates, including aspirin (Anacin, Ascriptin, Bayer Aspirin, Ecotrm) and salsalate (Mono-Gesic, Salgesic) ; non-steroidal anti-inflammatory drugs (NSAIDs); non-selective inhibitors of cyclooxygenase enzymes (COX-1 and COX-2), including diclofenac (Cataflam, Voltaren), ibuprofen (Advil, Motrin), ketoprofen (Orudis), naproxen (Aleve, Naprosyn), piroxicam (Feldene), etodolac (Lodine) , indomethacin, oxaprozin (Daypro), nabumetone (Relafen), and meloxicam (Mobic); selective cyclooxygenase-2 (COX-2) inhibitors, including Celecoxib (Celebrex); disease-modifying antirheumatic drugs (DMARDs), including azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), gold salts (Ridaura, Solganal, Aurolate, Myochrysine), hydroxychloroquine (Plaquenil), leflunomide (Arava), methotrexate (Rheumatrex), penicillamine (Cuprimine) and sulfasalazine (Azulfidine); biologic drugs including abatacept (Orencia), etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira) and anakinra (Kineret); corticosteroids, including betamethasone (Celestone Soluspan), cortisone (Cortone), dexamethasone (Decadron), methylprednisolone (SoluMedrol, DepoMedrol), prednisolone (Delta-Cortef), prednisone (Deltasone, Orasone), and triamcinolone (Aristocort); gold salts, including Auranofin (Ridaura); Aurothioglucose (Solganal); Aurolat; Myochrysin; or any combination thereof.

In one embodiment, the present invention provides a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of a composition containing a compound of the present 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 containing a compound of the present invention, in combination or in alternation with additional complement inhibitors. 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 containing a compound of the present invention, in combination or in alternation with corticosteroids. Examples of corticosteroids include, but are not limited to, prednisone, dexamethasone, solumedrol, and methylprednisolone.

In one embodiment of the invention, a compound of formula I is combined with at least one anti-multiple sclerosis drug selected from: Aubagio (teriflunomide), Avonex (interferon beta-1a), Betaseron (interferon beta-1b), Copaxone (glatiramer acetate), Extavia (interferon beta-1b), Gilenya (Fingolimod), Lemtrada (alemtuzumab), Novantrone (mitoxantrone), Plegridy (peginterferon beta-1a), Rebif (interferon beta-1a), Tecfidera (dimethyl fumarate), Tysabri (natalizumab), Solu -Medrol (methylprednisolone), high dose oral Deltasone (prednisone), N.R. Acthar Gel (ACTH) and their combinations.

In one aspect, a compound or salt of Formula I may be presented in combination or alternation with an immunosuppressant agent or an anti-inflammatory agent.

In one embodiment of the present invention, a compound described herein can be administered in combination or alternating with at least one immunosuppressive agent. The immunosuppressive agent may include, but is not limited to, an inhibitor

- 39 043505 calcineurin torus, e.g. cyclosporine or ascomycin, e.g. Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, mTOR inhibitor, e.g. rapamycin or its derivative, e.g. Sirolimus (Rapamune®), Everolimus (Certican®) , temsirolimus, zotarolimus, biolimus-7, biolimus-9, rapalog, e.g. ridaforolimus, azathioprine, campate 1H, S1P receptor modulator, e.g. fingolimod or analogue, anti-IL-8 antibody, mycophenolic acid or its salt, 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-deoxypergualine, 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, LFA3lg, etanercept (marketed as ENBREL® by Immunex), adalimumab (Humira®), infliximab (REMICADE®), anti-LFA-1 antibody, natalizumab (Antegren®), Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab , Alefacept efalizumab, pentase, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen.

Examples of anti-inflammatory agents include methotrexate, dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate, fluoromethalone acetate, fluoromethalone alcohol, lotoprendol etabonate, medrisone, prednisolone acetate, prednisolone sodium phosphate, difluprednate, rimexolone, hydrocortisone, hydrocortisone acetate, lodoxamide tromethamine, and spirin, ibuprofen, suprofen , piroxicam, meloxicam, flubiprofen, naproxan, ketoprofen, tenoxicam, diclofenac sodium, ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac, flurbiprofen sodium, suprofen, celecoxib, naproxen, rofecoxib, glucocorticoids, diclofenac and any combinations thereof. In one embodiment of the invention, 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 their combinations.

VI. Method for preparing compounds of formula I.

Abbreviations.

(VosDO ditertbutyl dicarbonate ACN Acetonitrile AcOEt, EtOAc ethyl acetate CH3OH, MeOH Methanol CsF Cesium fluoride Cui Copper iodide DCM,CH2CI2 Dichloromethane DIEA, DIPEA N,N-diisopropylethylamine DMA Ν,Ν-dimethyl acetamide DMF N,N-dimethylformamide DMSO Dimethyl sulfoxide DPPA Diphenylphosphoryl azide Et ₃ N,TEA Triethylamine EtOAc Ethyl acetate EtOH Ethanol HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- hexafluorophosphate oxide

- 40 043505

NS1 Hydrochloric acid ΨηΝΕΐ N,N-diisopropylethylamine K ₂ COz Potassium carbonate LiOH Lithium hydroxide MTBE Methyl tert-butyl ether _{Na2SO4 _} Sodium sulfate NaCl Sodium chloride NaH Sodium hydride _NaHCO3 Bicarbonate of soda NEt3 Trimethylamine Pd(OAc) ₂ Palladium acetate Pd(dppf) _Cl2 [ 1, G-Bis(diphenylphosphino)ferrocene] dichloro palladium(P) Pd(PPh ₃ ) ₂ C12 Bis(triphenylphosphine)palladium(P) dichloride Pd(PPh ₃ ) ₄ Tetrakis(triphenylphosphate)alladium(0) Pd ₂ (dba) ₃ Tris(dibeisylideneacetone)dipalladium(0) PPh ₃ Triphenylphosphine K.T. Room temperature tBuOK Potassium tertbutoxide TEA Trimethylamine T.F.A. trifluoroacetic acid _Tf2O trifluoromethanesulfonic anhydride T.F.A. Trifluoroacetic acid THF T ethrahydrofuran TMSBr Bromotrimethylsilane fa Retention time Zn(CN) ₂ Zinc cyanide

General methods.

All non-aqueous reactions were carried out under dry argon or nitrogen gas using anhydrous solvents. The progress of the reactions and the purity of the target compounds were determined using one of the two liquid chromatography (LC) methods given below. The structure of the starting materials, intermediates and final products was confirmed by standard analytical techniques, including NMR spectroscopy and mass spectrometry.

Method A. LC.

Device: Waters Acquity Ultra Performance LC.

Column: ACQUITY UPLC VEN C18 2.1x50 mm, 1.7 µm.

Column temperature: 40°C.

Mobile phase: solvent A: H ₂ O+0.05% FA; solvent B: CH ₃ CN + 0.05% FA.

Flow rate: 0.8 ml/min.

Gradient: 0.24 min @ 15% V, 3.26 min gradient (15-85% V), then 0.5 min @ 85% V.

Detection: UV (PDA), ELS and MS (SQ in EI mode).

Method B. LC.

Device: Shimadzu LC-2010A NT.

Column: Athena, C18-WP, 50x4.6 mm, 5 µm.

Column temperature: 40°C.

Mobile phase: solvent A: H ₂ O/CH ₃ OH/FA=90/10/0.1; solvent B:

H ₂ O/CH ₃ OH/FA = 10/90/0.1.

Flow rate: 3 ml/min.

Gradient: 0.4 min @ 30% B, 3.4 min gradient (30-100% B), then 0.8 min @ 100% B.

Detection: UV (220/254 nm).

Example 1. General synthesis route.

The compound of the present invention can be obtained, for example, from the central core. IN

- 41 043505 In one embodiment of the invention, for example, the central core of structure 1 is an N-protected amino acid, where X ¹ represents nitrogen and PG = protecting group. In one embodiment of the invention, the central core is added to an amine to produce an amide of structure 2 (where LB includes a C(O)N moiety). Structure 2 can then be deprotected to produce structure 3. Structure 3 is added to structure 4 (A-COOH) to form a second amide bond, forming a compound within Formula I. The chemistry is illustrated in Route 1.

activation Q ¹ ^ ^Q \

CO ₂ H\ _/ ^x< -r'··'·' removal

Q....

accession | ρθ

PQ .amine PG

Structure 1 Structure 2 qi-Q^ A-COOH θ · _χ ,._ ... in ' LA..,,/ ⁶ (Structure 4) Q'/ (M / ^L ---------- ------► L

Structure 3

Formula I

Route 1

Alternatively, the central core of structure 5 is reacted with a heterocyclic or heteroaryl compound to produce a compound of structure 6. In one embodiment, structure 6 is deprotected to yield a carboxylic acid, structure 7. In one embodiment, structure 7 is coupled to an amine to yield a compound formula I. This chemistry is illustrated in route 2.

ηΐ-θ ¹ 1

I A3PG ™ _{clear_}

L L attachment Q\

II dilution ^L ηΑ removal /O * ^X ¹ II ———*

O ( ___/ O PG^

G.L.

Structure 5 Structure 6

Ql^ ^Q y Q ¹ ^ ^Q \

I ,OH attached - I \ ₂ .B

I / dining L / ^; x' Ί* ⁰ /

A.A.

Structure 7 Formula I

Route 2

In an alternative embodiment, structure 8 is deprotected to form an amine, which is structure 9. Structure 9 is then coupled to form an amide, which is structure 6. Structure 6 is deprotected to produce a carboxylic acid, which is structure 7. Structure 7 is then coupled to form an amide, which falls under Formula I. The chemistry is illustrated in Route 3.

□’•°· at

ABOUT:

About PG pg ₂

Structure 8 ,OPG

Q'· ⁰ ' removal । .OPG

PG ₂

O ¹ -,

ABOUT

Structure 9 removal

A Structure b

A-COOH (structure 4) accession / ^he

Τί accession

A

Structure 7

Q ¹

Qi

Q ¹

V.B

X'

O

A

Formula I

Route 3

In an alternative embodiment of the invention, the heteroaryl or aryl moiety 4-1

- 42 043505 is added to the central core to obtain 4-2. The protected acid, 4-2, is deblocked to form the carboxylic acid, 4-3. A carboxylic acid is then added to form an amide (LB), which is 4-4. The heteroaryl or aryl moiety, A', can then be further used to add substituents at the ^X11 , ^X12 , ^X13 and ^X14 positions to produce compounds of Formula I. This chemistry is illustrated in Route 4.

v2 ^OPG

0041 accession

Route 4

In an alternative embodiment of the invention, structure 5-1 is coupled to an acid, structure 5-2, to form structure 5-3. The carboxylic acid, structure 5-3, is deblocked to give the carboxylic acid, which is structure 5-4. A carboxylic acid with structure 5-4 is added to an amine to form an amide product (L-B), which is a compound within Formula I. This chemistry is illustrated in Route 5.

Q ¹

A-COOH ' ^irb Structure 5-2 ac _x ,' ,OPG removal ^Q ¹

U^ ^he

-'X ¹ ' G

ABOUT

Structure. 5-1

PG.

Ο· activation

CO^H addition of amine

Q\ _x ,' :O

A

Structure 5-3

A

Structure 5-4,β

Formula I

Route 5

In an alternative embodiment of the invention, the heteroaryl compound of structure 10 is acylated to produce a compound of structure 11, in which LG is a leaving group. By way of example, the leaving group may be a halide, such as a bromide. Structure 11 is added to structure 12 to form structure 13. In some embodiments, LG ₁ is a leaving group. In some embodiments, LG ₁ is a halide. Structure 13 is attached to an aryl, heteroaryl, or heterocyclic compound to form structure 14. In some embodiments, structure 13 is treated with an aryl, heteroaryl, or heterocyclic boronic acid, an organometallic catalyst, a base, and an organic solvent. In some embodiments, the organometallic catalyst is tetrakis(triphenylphosphine)palladium(0). In some embodiments of the invention, the base is cesium carbonate. In some embodiments of the invention, the organic solvent is DMF. Structure 14 is treated with an organic acid, such as, but not limited to, trifluoroacetic acid, to yield structure 15. Structure 15 is coupled to structure 3 from Route 1 to yield a compound within Formula I. This chemistry is illustrated in Route 6.

- 43 043505

In an alternative embodiment of the invention, the heteroaryl compound of structure 17 is acylated to produce a compound of structure 18 in which LG is a leaving group. By way of example, the leaving group may be a halide, such as a bromide. Structure 18 is coupled to an activated ester, structure 12, from route 6, in which LG1 may be a halogen, to give structure 19.

Structure 19 is attached to an aryl, heteroaryl, or heterocyclic compound to form structure 20. In some embodiments, structure 19 is treated with an aryl, heteroaryl, or heterocyclic boronic acid, an organometallic catalyst, a base, and an organic solvent. In some embodiments, the organometallic catalyst is tetrakis(triphenylphosphine)palladium(0). In some embodiments of the invention, the base is cesium carbonate. In some embodiments of the invention, the organic solvent is DMF. Structure 20 is treated with an organic acid, such as, but not limited to, trifluoroacetic acid, to yield structure 21. Structure 21 is coupled to structure 3 from Route 1 to yield a compound within Formula I. This chemistry is illustrated in Route 7.

^R3O

Structure 17 Structure 18

- 44 043505

Structure 19 Structure 20

Structure 21

Formula I

Route 7

In an alternative embodiment of the invention, a heteroaryl compound of structure 8-1 is acylated to produce a compound of structure 8-2 in which LG is a leaving group. By way of example, the leaving group may be a halide, such as a bromide. Structure 8-2 is added to structure 8-3 to form structure 8-4. In some embodiments of the invention, LG ₁ is a leaving group. In some embodiments, LG ₁ is a halide.

Structure 8-4 is added to an aryl, heteroaryl or heterocyclic compound to produce structure 8-5. In some embodiments, structure 8-4 is treated with an aryl, heteroaryl, or heterocyclic boronic acid, an organometallic catalyst, a base, and an organic solvent. In some embodiments, the organometallic catalyst is tetrakis(triphenylphosphine)palladium(0). In some embodiments of the invention, the base is cesium carbonate. In some embodiments of the invention, the organic solvent is DMF. Structure 8-5 is treated with an organic acid, such as, but not limited to, trifluoroacetic acid, to obtain structure 8-6. Structure 8-6 is added to structure 3 from Route 1 to produce a compound within Formula I. This chemistry is illustrated in Route 8.

- 45 043505

In an alternative embodiment of the invention, a heteroaryl compound of structure 9-1 is acylated to produce a compound of structure 9-2, in which LG is a leaving group. By way of example, the leaving group may be a halide, such as a bromide. Structure 9-2 is coupled to an activated ester, structure 9-3, in which LG1 may be a halide, to give structure 9-4. Structure 9-4 is added to an aryl, heteroaryl or heterocyclic compound to produce structure 9-5. In some embodiments, structure 9-4 is treated with an aryl, heteroaryl, or heterocyclic boronic acid, an organometallic catalyst, a base, and an organic solvent. In some embodiments, the organometallic catalyst is tetrakis(triphenylphosphine)palladium(0). In some embodiments of the invention, the base is cesium carbonate. In some embodiments of the invention, the organic solvent is DMF. Structure 9-5 is treated with an organic acid, such as, but not limited to, trifluoroacetic acid, to obtain structure 9-6. Structure 9-6 is added to structure 3 from Route 1 to produce a compound within Formula I. This chemistry is illustrated in Route 9.

- 46 043505

In an alternative embodiment of the invention, structure 10-1 is coupled to an amine to form an amide (L-B) and structure 10-2. Structure 10-2 is coupled to an amine to produce compounds within Formula I. This chemistry is illustrated in Route 10.

soon soon

10-1

Route 10

Example 2. Examples of central syntons.

- 47 043505

Z ^A represents halogen.

In one embodiment of the invention, deuterated L-proline synthons are disclosed. Deuterated synthons include, but are not limited to, for example the following compounds:

Structure A can be treated with deuterium oxide to produce 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 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 give structure D. Structure B can be treated with DAST to give structure E. See WO 2014/037480. Structure A can be treated with sodium borodeuteride to give structure F. See Dormoy, J.-R.; Castro, V. Synthesis 1986, 81-82. Compound F can be used to obtain structure K. See Dormoy, J.-R.; Castro, V. Synthesis 1986, 81-82. Structure B can be treated with a deuterated reducing agent, such as sodium borodeuteride, to give structure G. Structure G can be treated with DAST to give structure H. Structure F can be used to give structure K. See Dormoy, J. -R.; Castro, V. Synthesis 1986, 81-82. Structure G can be used to make structure I. Structure J can be made according to Hruby, V. J. et al. J. Am. Chem. Soc. 1979, 101, 202-212. Structures A-J can be used to prepare compounds of formula I.

Example 3. Obtaining central-L-B syntons.

- 48 043505

Routes la, 1b and 1c.

In route 1a, 5-(1,1-dimethylethyl) 5-azaspiro[2,4]heptane-4,5-dicarboxylic acid ester, (4S)-, CAS 209269-08-9, can be prepared as described in Tandon, M. et al. Bioorg. Med. Chem. Lett. 1998, 8, 1139-1144. In step 2, the protected azaspiro[2,4]heptane is added to the amine in the presence of an organic solvent, a base and a condensing reagent to form an amide bond; remainder L-B. In one embodiment of the invention, the amine is (3-chloro-2fluorophenyl)methanamine. In one embodiment of the invention, the organic solvent is DMF. In one embodiment of the invention, the base is diisopropylethylamine. In one embodiment of the invention, the condensing reagent is HATU. In step 3, the protecting group is removed. In one embodiment of the invention, the starting material reacts with an acid in the presence of an organic solvent. In one embodiment of the invention, the acid is 4N. hydrochloric acid. In one embodiment of the invention, the organic solvent is dioxane.

In route 1b, (4S)-4-oxazolidinecarboxylic acid hydrochloride is treated with an amine protecting reagent. In one embodiment of the invention, the amine protecting agent is di-tert-butyl dicarbonate. In another embodiment of the invention, 3-(1,1-dimethylethyl) 3,4-oxazolidinedicarboxylic acid ester, (4S)-, is commercially available from JPM2 Pharmaceuticals. In one embodiment of the invention, the reaction is carried out in an organic solvent in the presence of a base. In one embodiment of the invention, the organic solvent is acetonitrile. In one embodiment of the invention, the base is 4-dimethylaminopyridine (DMAP). In Step 2, a protected 4-oxazolidinecarboxylic acid is added to an amine in the presence of an organic solvent, a base, and a condensing reagent to form an amide bond; remainder L-B. In one embodiment of the invention, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment of the invention, the organic solvent is DMF. In one embodiment of the invention, the base is diisopropylethylamine. In one embodiment of the invention, the condensing reagent is HATU. In step 3, the protecting group is removed. In one embodiment of the invention, the starting material reacts with an acid in the presence of an organic solvent. In one embodiment of the invention, the acid is 4N. hydrochloric acid. In one embodiment of the invention, the organic solvent is dioxane.

In route 1c, (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid, CAS 1129634-44-1, is commercially available from Ark Pharm. In step 2, a carboxylic acid is added to an amine in the presence of an organic solvent, a base, and a condensing reagent to form an amide bond; remainder L-B. In one embodiment of the invention, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment of the invention, the organic solvent is DMF. In one embodiment of the invention, the base is diisopropylethylamine. In one embodiment of the invention, the condensing reagent is HATU. In step 3, the protecting group is removed. In one embodiment of the invention, the starting material reacts with an acid in the presence of an organic solvent. In one embodiment of the invention, the acid is 4N. hydrochloric acid. In one embodiment of the invention, the organic solvent is dioxane.

- 49 043505

Routes 2a, 2b, 2c and 2d.

In route 2a, commercially available Boc-L-proline is added to an amine in the presence of an organic solvent, a base, and a condensing reagent to form an amide bond; remainder L-B. In one embodiment of the invention, the amine is (3-chloro-2fluorophenyl)methanamine. In one embodiment of the invention, the organic solvent is DMF. In one embodiment of the invention, the base is diisopropylethylamine. In one embodiment of the invention, the condensing reagent is HATU. In step 3, the Boc protecting group is removed. In one embodiment of the invention, the starting material reacts with an acid in the presence of an organic solvent. In one embodiment of the invention, the acid is 4N. hydrochloric acid. In one embodiment of the invention, the organic solvent is dioxane.

In route 2b, commercially available (1R,3S,5R)-2-[(tert-butoxy)carbonyl]-2azabicyclo[3.1.0]hexane-3-carboxylic acid from Enamine is coupled to an amine in the presence of an organic solvent, a base, and a condensing reagent to obtain an amide bond; remainder L-B. In one embodiment of the invention, the amine is (3-chloro-2fluorophenyl)methanamine. In one embodiment of the invention, the organic solvent is DMF. In one embodiment of the invention, the base is diisopropylethylamine. In one embodiment of the invention, the condensing reagent is HATU. In step 2, the Boc protecting group is removed. In one embodiment of the invention, the starting material reacts with an acid in the presence of an organic solvent. In one embodiment of the invention, the acid is 4N. hydrochloric acid. In one embodiment of the invention, the organic solvent is dioxane.

In route 2c, commercially available (2s,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2carboxylic acid from Manchester Organics is coupled to an amine in the presence of an organic solvent, base and condensing reagent to form an amide bond; remainder L-B. In one embodiment of the invention, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment of the invention, the organic solvent is DMF. In one embodiment of the invention, the base is diisopropylethylamine. In one embodiment of the invention, the condensing reagent is HATU. In step 2, the Boc protecting group is removed. In one embodiment of the invention, the starting material reacts with an acid in the presence of an organic solvent. In one embodiment of the invention, the acid is 4N. hydrochloric acid. In one embodiment of the invention, the organic solvent is dioxane.

In route 2d, commercially available (8)-1-(tert-butoxycarbonyl)indoline-2-carboxylic acid from Chem-Impex is coupled to an amine in the presence of an organic solvent, base and condensing reagent to form an amide bond; remainder L-B. In one embodiment of the invention, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment of the invention, the organic solvent is DMF. In one embodiment of the invention, the base is diisopropylethylamine. In one embodiment of the invention, the condensing reagent is HATU. In step 2, the Boc protecting group is removed. In one embodiment of the invention, the starting material reacts with an acid in the presence of an organic solvent. In one embodiment of the invention, the acid is 4N. hydrochloric acid. In one embodiment of the invention, the organic solvent

- 50 043505 is dioxane. This chemistry is illustrated in Scheme 2.

Additional starting materials that can be readily converted to Central-L-BSynthons include, but are not limited to: (S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2carboxylic acid, CAS 90104- 21-5, available from Ark Pharm; cyclopent-1-ene-1,2-dicarboxylic acid, CAS 3128-15-2, purchased from Ark Pharm; imidazole, 1H-imidazole-1,2-dicarboxylic acid, 1-(1,1-dimethylethyl)2-ethyl ester, CAS 553650-00-3, commercially available from FCH Group; Boc-Loctahydroindole-2-carboxylic acid, which can be purchased from Chem Impex. Compound

can be obtained in accordance with the methods described in WO 2004/111041; (S)Boc-5-oxopyrrolidine-2-carboxylic acid is available from Aldrich Chemical Co.; (1S,2S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]hexane-2-carboxylic acid is available from Ark Pharm; (S)-3-bocthiazolidine-2-carboxylic acid is available from Alfa Aesar; (2S,4R)-1-(tert-butoxycarbonyl)-4chloropyrrolidine-2-carboxylic acid is available from Arch Bioscience; (1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid is available from Ark Pharm; 1,2pyrrolidinedicarboxylic acid, 3-[[(phenylmethoxy)carbonyl]amino]-,1-(1,1-dimethylethyl)ester, (2S,3R) can be prepared as described in WO 2004/007501. The Cbz group can be removed and the amino group can be alkylated to produce the central core compounds of the present invention.

Compound

can be prepared as described in Braun, J.V.; Heymons, Albrecht Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1930) 63B, 502-7.

Compounds (2S,3S,4S)-4-fluoro-3-methoxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)-3-fluoro-4-methoxypyrrolidine-1,2 α-dicarboxylic acid 1-tert-butyl ester can be prepared as a mixture according to Novartis WO 2012/093101 and the regioisomers can ultimately be separated from each other by being coupled to form the central core-L-B synthons. The compound (S)-voc-5-oxopyrrolidine-2-carboxylic acid is available from Aldrich Chemical Co.

Example 4. Synthesis of aryl, heteroaryl and heterocyclic compounds of formula I.

Synthesis of (2S,4R)-1-(2-(3-acetyl-5-(2-methoxypyridin-5-yl)-1H-indol-1-yl)acetyl)-N-(2'-chloro-2fluoro- [1,1'-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamide (27).

Scheme 1

Br

SnCU AcCI

Toluene

N

J 1

......G^vg

CHjCH

Br

P<ЦРРь ₃ )4,С$гСО ₃

BUT but ⁱⁿ C ° ^сн » ^F _r - ₄ HNC; _t mg,

-N O όι but

NATO, NEA, BMP

4M on Dioisan

R O

Ν- _τ

027 y···N 'n ⁴ och ₃ y ^A basic _;

E

-x HN^

N O N

Ts g/osnz

R-O AND T-VUTSHE

7:3 Mix Shosla and Ether

NS1 6

1-(5-bromo-1H-indol-3-yl)ethanone (2) was prepared from 5-bromoindole according to the procedure described by MacKay et al. (MacKay, J. A.; Bishop, R.; Rawal, V. H. Org. Lett. 2005, 7, 3421-3424).

tert-Butyl-2-(3-acetyl-5-bromo-1H-indol-1-yl)acetate (3).

A mixture of 3.9 g (16.4 mmol) 1-(5-bromo-1H-indol-3-yl)ethanone, 2.63 ml (18.02 mmol) tert-butyl bromoacetate and 2.50 g (18.02 mmol) potassium carbonate in anhydrous acetonitrile (80 ml) was refluxed for 5 hours. The reaction mixture was then cooled to room temperature. and the solvent was removed under reduced pressure. The residue was dissolved in a 1:1 mixture of CH ₂ Cl ₂ and water (100 ml: 100 ml). The two layers were separated and the organic layer was washed with water (2x100 ml). Finally, the organic layer was dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was stirred with 50 ml of heptane for 30 minutes, cooled in an ice bath and filtered, washing the solid with cold heptane (10 ml). This cream-colored solid was dried under high vacuum to obtain 5.6 g of tert-butyl-2-(3

- 51 043505 acetyl-5-bromo-1 H-indol-1 -yl)acetate.

tert-Butyl-2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-1 H-indol-1 -yl)acetate (4).

A mixture of 351 mg (1 eq.) of 3, (2-methoxypyrimidin-5-yl)boronic acid (230 mg, 1.5 eq.), cesium carbonate (650 mg, 2 eq.) in DMF (15 ml) and water ( 1.5 ml) was purged with argon in a pressure vessel for 5 min. Tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.05 eq.) was then added under argon and the pressure vessel was sealed and heated at 100° C. overnight. The reaction mixture was cooled to room temperature. and the solvent was removed under reduced pressure. The crude product (7:3 mixture of acid and ester) was used directly in the next stage of the synthesis.

2-(3-Acetyl-5-(2-methoxypyrimidin-5-yl)-1H-indol-1-yl) acetic acid (5).

Take tert-butyl-2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-1H-indol-1-yl)acetate (crude product of the above reaction) in 4N. HCl in dioxane (20 ml) and the resulting reaction mixture was stirred at room temperature. for 4 hours. After completion of the reaction, the solvent was removed under reduced pressure. The remaining material was used directly in the next stage of the synthesis.

(2S,4R)-1-(2-(3-acetyl-5-(2-methoxynirimidin-5-yl)-1H-indol-1-yl)acetyl)-N-(2'-chloro-2-fluoro [1,1'-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamide (27).

Compound 5 (100 mg, 1 eq.) from the previous step was dissolved in DMF (10 ml) and iPr ₂ NEt (0.269 ml, 5 eq.) was added followed by the addition of (2S,4R)-N-(3-chloro-chloride) hydrochloride (2S,4R)-N-(6chloropyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (111 mg, 1 eq.) at 5° C. HATU (263 mg, 2 eq.) was then slowly added at the same temperature ,1 eq.) and the reaction mixture was stirred for 3 hours at RT After completion of the reaction, monitored by HPLC, the reaction mixture was added to water (50 ml + 10 g NaCl) and extracted with DCM (2x25 ml). The organic layer was washed successively with aqueous NaHCO ₃ (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure.The remaining residue was purified using flash column chromatography (ISCO elute with DCM/CH3OH) to give 7. ^1H NMR (400 MHz, DMSO-d6, 300 K): (main rotamer) δ 2.13-2.3 (m, 1H), 2.45 (s, 3H ), 2.68-2.70 (m, 1H), 3.95-4.05 (m, 4H), 4.16-4.24 (m, 1H), 4.78 (t, J=8 Hz, 1H), 5.28 (d, J=20 Hz, 1H), 5.45 (d, J=20 Hz, 1H), 5.50-5.63 (m, 1H), 7.04- 7.08 (m, 1H), 7.20-7.24 (m, 1H), 7.37-7.61 (m, 7H), 7.75-7.78 (m, 1H), 7. 94-7.98 (m, 1H), 8.31 (s, 1H), 8.88 (s, 1H), 8.97 (s, 1H); 19F NMR (376 MHz, DMSO-d6, 300 K): (main rotamer) δ 126.64, -175.79.LC (method A): tR=2.16 min. LC/MS (EI) m/z: [M+H] ⁺ calc. for C34H ₂₈ ClF ₂ N ₅ O ₄ , 643; 644 found.

Scheme 2

BUT _β .ΟΗ ₽ ,α f

УУ U ⁸ , ™yy

K _? co.,, Pdidppf^С1., Diskgan

10

2'-Chloro-2-fluoro-[1,1'-biphenyl]-3-amine hydrochloride (10).

A mixture of 8 (30 g), 9 (60 g), K2CO3 (91 g) and Pd(dppf) ₂ Cl ₂ (19.25 g) in a solvent (dioxane 400 ml, H ₂ O 100 ml) was purged with argon in a high-pressure vessel pressure for 5 minutes and stirred for 15 hours at 100°C. The solvent was removed under reduced pressure and the resulting residue was purified using flash column chromatography. The purified material was then dissolved in MeOH and treated with HCl/MeOH. The solvent was removed and the remaining solid was washed with IPA-heptane (1/1) to give 10.

(2S,4R)-tert-butyl-2-((2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidine-1carboxylate (12).

To an ice-cooled solution of 11 (530 mg) in 20 ml CH ₂ Cl ₂ was added 1-chloro-N,N,2-trimethyl-1-propenylamine (0.333 ml, 1.1 eq.) dropwise with stirring. Stirring was continued for 3 hours at this temperature, then solid 10 (640 mg, 1.1 eq) and then 1.12 ml iPr ₂ NEt (3 eq) were added. The cooling bath was removed and the reaction mixture was stirred overnight at room temperature. After completion of the reaction as monitored by HPLC, the reaction mixture was added to water (20 ml) and extracted with DCM (2x25 ml). The organic layer was washed successively with aqueous NaHCO3 (20 ml), water (20 ml) and brine (20 ml), then dried over Na2SO4 and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (ISCO eluted with Hexanes/EtOAC) to give 12.

(2S,4R)-N-(2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)-4-fluoropyrrolidin-2-carboxamide hydrochloride (6).

Take (2S,4R)-tert-butyl-2-((2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidine-1carboxylate 12 (700 mg) at 4am HCl in dioxane (25 ml) and the resulting reaction mixture was stirred at room temperature. for 3 hours. After completion of the reaction, monitored by HPLC, the solvent was removed under reduced pressure. The remaining residue 6 was used directly in the next synthesis step (preparation 7).

Example 5 Additional syntheses of aryl, heteroaryl and heterocyclic compounds of formula I.

Scheme 1

Step 1: 1-(5-bromo-1H-indol-3-yl)ethanone.

The title compound was prepared from 5-bromoindole according to the procedure described by MacKay et al. (MacKay, J. A.; Bishop, R.; Rawal, V. H. Org. Lett. 2005, 7, 3421-3424.)

Step 2: tert-butyl-2-(3-acetyl-5-bromo-1H-indol-1-yl) acetate.

A mixture of 1-(5-bromo-1H-indol-3-yl)ethanone (3.9 g, 16.4 mmol), tert-butyl bromoacetate (2.63 ml, 18.02 mmol) and potassium carbonate (2.50 g, 18.02 mmol) in anhydrous acetonitrile (80 ml) was refluxed for 5 hours. The reaction mixture was then cooled to room temperature. and the solvent was removed under reduced pressure. The residue was dissolved in a 1:1 mixture of DCM and water (100 ml: 100 ml). The two layers were separated and the organic layer was washed with water (2x100 ml). Finally, the organic layer was dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was stirred with 50 ml of heptane for 30 minutes, cooled in an ice bath and filtered, washing the solid with cold heptane (10 ml). This cream-colored solid was dried under high vacuum to obtain 5.6 g of tert-butyl-2-(3-acetyl-5-bromo1 H-indol-1-yl)acetate.

Step 3: tert-butyl-2-(3-acetyl-5-(pyridazin-4-yl)-1H-indol-1-yl)acetate.

Mixture of tert-butyl-2-(3-acetyl-5-bromo-1H-indol-1-yl)acetate (351 mg, 1 eq.), 4-(4,4,5,5-tetramethyl1,3,2 -dioxaborolan-2-yl)pyridazine (250 mg, 1.5 equiv), cesium carbonate (700 mg, 2 equiv), DMF (15 ml) and water (1.5 ml) were purged with argon in a pressure vessel for 5 min. Tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.05 eq.) was then added under argon and the pressure vessel was sealed and heated at 100° C. overnight. The reaction mixture was cooled to room temperature. and the solvent was removed under reduced pressure. The crude product was used directly in the next stage of the synthesis.

Step 4: 2-(3-Acetyl-5-(pyridazin-4-yl)-1H-indol-1-yl)acetic acid.

Take tert-butyl-2-(3-acetyl-5-(pyridazin-4-yl)-1H-indol-1-yl)acetate (crude from the above reaction) in 4N. HCl in dioxane (20 ml), and the resulting reaction mixture was stirred at room temperature. for 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Step 5: (2S,4R)-1-(2-(3-Acetyl-5-(pyridazin-4-yl)-1H-indol-1-yl)acetyl)-N-(2'-chloro-2- fluoro[1,1'-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamide (20).

2-(3-Acetyl-5-(pyridazin-4-yl)-1H-indol-1-yl)acetic acid (100 mg, 1 eq.) was dissolved in DMF (10 ml) and DIEA (0.269 ml, 5 eq.) followed by the addition of hydrochloride (2S,4R)-N(3-chloro-(2S,4R)-N-(6-chloropyridin-2-yl)-4-fluoropyrrolidin-2-carboxamide (111 mg, 1 eq. .) at a temperature of 5° C. Then, at the same temperature, HATU (263 mg, 2.1 eq.) and the reaction

- 53 043505 the mixture was stirred for 3 hours at room temperature. The reaction mixture was then added to water (50 ml + 10 g solid NaCl) and extracted with DCM (2x25 ml). The organic layer was washed successively with aqueous NaHCO ₃ (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (eluted with DCM/MeOH) to give ^20.1H NMR (400 MHz, DMSO-d6, 300 K): (main rotamer) δ 2.13-2.30 (m, 1H), 2.45 ( s, 3H), 2.58-2.68 (m, 1H), 3.95-4.05 (m, 1H), 4.13-4.22 (m, 1H), 4.75 (t, J=8 Hz, 1H), 5.28 (d, J= 20 Hz, 1H), 5.45 (d, J=20 Hz, 1H), 5.50-5.63 (m, 1H), 7.067.10 (m, 1H), 7.31-7.49 (m, 4H), 7.51-7.61 (m , 1H), 7.65-7.80 (m, 1H), 7.92-8.03 (m, 2H), 8.35 (s, 1H), 8.61 (s, 1H), 9.23 (d, 1H), 9.61 (s, 1H), 9.97 (s, 1H); ¹⁹ F NMR (376 MHz, DMSO-d6, 300 K): (main rotamer) δ 126.74, -175.78. LC (method A): tR=2.58 min. LC/MS (EI) m/z: [M+H] ⁺ 614.

Scheme 2

Step 1: 2'-chloro-2-fluoro-[1,1'-biphenyl]-3-amine hydrochloride.

A mixture of 3-bromo-2-fluoroaniline (30 g), (2-chlorophenyl)boronic acid (60 g), K2CO3 (91 g) and Pd(dppf) ₂ Cl ₂ (19.25 g) in a solvent (dioxane 400 ml , H ₂ O 100 ml) was purged with argon in a pressure vessel for 5 minutes and stirred for 15 hours at 100°C. The solvent was removed under reduced pressure and the remaining residue was purified using flash column chromatography. The purified material was then dissolved in MeOH and treated with HCl/MeOH. The solvent was removed and the remaining solid was washed with IPA-heptane (1/1) to give the title compound.

Step 2: (2S,4R)-tert-butyl-2-((2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)carbamoyl)-4fluoropyrrolidine-1-carboxylate.

1-χλορ-N,N,2 trimethyl- 1-propenylamine (0.333 ml, 1.1 eq.). Stirring was continued for 3 hours at this temperature and then solid 2'-chloro-2-fluoro-[1,1'-biphenyl]-3-amine hydrochloride (640 mg, 1.1 eq.) was added followed by DIEA ( 1.12 ml, 3 eq.). The cooling bath was removed and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then added to water (20 ml) and extracted with DCM (2x25 ml). The organic layer was washed successively with aqueous NaHCO3 (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (eluted with hexanes/EtOAc) to give (2S,4R)-tert-butyl-2-((2'-chloro-2-fluoro-[1,1'-biphenyl]-3yl )carbamoyl)-4-fluoropyrrolidine-1-carboxylate.

Step 3: (2S,4R)-N-(2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)-4-fluoropyrrolidin-2carboxamide hydrochloride.

Take (2S,4R)-tert-butyl-2-((2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidine-1carboxylate (700 mg) in 4n. HCl in dioxane (25 ml), and the resulting reaction mixture was stirred at room temperature. for 3 hours. The solvent was removed under reduced pressure and the remaining residue was used directly in the next stage of the synthesis.

Scheme 3

- 54 043505

Step 1: 5-Bromo-1H-indole-3-carboxamide.

A mixture of 5-bromo-1H-indole-3-carbonitrile (10 g) in TFA (160 ml) and sulfuric acid (40 ml) was stirred at room temperature for 4 hours. The reaction mixture was then poured into ice and a solid precipitated the material was collected by filtration, washed with water and dried in vacuo to give 5bromo-1H-indole-3-carboxamide.

Step 2: tert-butyl 2-(5-bromo-3-carbamoyl-1H-indazol-1-yl) acetate.

A mixture of 5-bromo-1H-indole-3-carboxamide (9.8 g, 41.66 mmol), tert-butyl bromoacetate (6.67 ml, 1.1 eq.) and potassium carbonate (6.32 g, 1.1 eq. 1 eq.) in anhydrous acetonitrile (100 ml) was refluxed for 5 hours. The reaction mixture was then cooled to room temperature. and the solvent was removed under reduced pressure. The residue was dissolved in a mixture of DCM and water. The two layers were separated and the organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated. The remaining residue was purified by flash column chromatography (eluted with DCM/MeOH) to give tert-butyl-2-(5-bromo-3carbamoyl-1H-indazol-1-yl)acetate.

Scheme 4

Step 1: tert-butyl-2-(3-carbamoyl-5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)acetate.

Mixture of tert-butyl 2-(5-bromo-3-carbamoyl-1H-indazol-1-yl)acetate (211 mg, 1 eq.), 4-(4,4,5,5tetramethyl-1,3,2 -Dioxaborolan-2-yl)-III-pyrazole (140 mg), cesium carbonate (391 mg, 2 equiv), DMF (10 ml) and water (1.0 ml) were purged with argon in a pressure vessel for 5 min. Tetrakis(triphenylphosphine)palladium(0) (35 mg) was then added under argon and the pressure vessel was sealed and heated at 100° C. overnight. The reaction mixture was cooled to room temperature. and the solvent was removed under reduced pressure. The crude product was used directly in the next stage of the synthesis.

Step 2: 2-(3-carbamoyl-5-(1H-nirazol-4-yl)-1H-indazol-1-yl)acetic acid.

Take tert-butyl-2-(3-carbamoyl-5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)acetate (crude from the above reaction) in 4N. HCl in dioxane (5 ml) and the resulting reaction mixture was stirred at room temperature. for 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Step 3: 1-(2-((2S,4R)-2-((2'-chloro-2-fluoro-[1,1'-biphenyl)carbamoyl)-4-fluoronirrolidin-1-yl)-2oxoethyl) -5-(1H-pyrazol-4-yl)-1H-indazol-3-carboxamide (1).

2-(3-carbamoyl-5-1H-(πyrazol-4-yl)-1H-indazol-1-yl)acetic acid (100 mg, 1 eq.) was dissolved in DMF (10 ml) and DIEA (0.269 ml) was added , 5 equiv.) followed by the addition of (2S,4R)N-(3-chloro-(2S,4R)-N-(6-chloropyridin-2-yl)-4-fluoropyrrolidin-2-carboxamide hydrochloride (111 mg, 1 eq) at 5° C. HATU (263 mg, 2.1 eq) was then slowly added at the same temperature and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was then added to water (50 ml + 10 g solid NaCl) and extracted with DCM (2x25 ml).The organic layer was washed successively with aqueous NaHCO ₃ (20 ml), water (20 ml) and saline (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure.The remaining residue was purified by flash column chromatography (eluted with DCM/MeOH) to give 1. Ή NMR (400 MHz, _DMSOd6 , 300 K): (main rotamer) δ 2.01-2.21 (m, 1H) , 2.49-2.55 (m, 1H), 3.80-3.92 (m, 1H), 4.08-4.21 (m, 1H), 4.61 (t, 1H), 5.47-5.62 (m, 3H), 7.05 (t, 1H) , 7.15 (t, J=8.0 Hz, 1H), 7.31-7.40 (m, 4H), 7.49-7.62 (m, 5H), 7.77 (m, 1H), 8.21 (s, 1H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ , 300K): (main rotamer) δ -126.75, -175.87. LC (me

- 55 043505 tod A): tR=1.79 min. LC/MS (E1) m/z: [M+H]+ 604.

Scheme 5

HCI stage 3

Step 1: tert-butyl-2-(3-carbamoyl-5-(pyrimidin-5-yl)-1H-indazol-1-yl) acetate.

Blend of tert-butyl 2-(5-bromo-3-carbamoyl-1H-indazol-1-yl)acetate (211 mg), pyrimidin-5ylboronic acid (82 mg), cesium carbonate (391 mg, 2 eq), DMF (9 ml) and water (1.0 ml) were purged with argon in a pressure vessel for 5 min. Tetrakis(triphenylphosphine)palladium(0) (40 mg) was then added under argon and the pressure vessel was sealed and heated at 100° C. overnight. The reaction mixture was cooled to room temperature. and the solvent was removed under reduced pressure. The crude product was used directly in the next stage of the synthesis.

Step 2: 2-(3-carbamoyl-5-(pyrimidin-5-yl)-1H-indazol-1-yl)acetic acid.

Take tert-butyl-2-(3-carbamoyl-5-(pyrimidin-5-yl)-III-indazol-1-yl) acetate (crude from the above reaction) in 4N. HCl in dioxane (5 ml) and the resulting reaction mixture was stirred at room temperature. for 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Step 3: 1 -(2-((2S,4R)-2-((2'-chloro-2-fluoro-[1,1'-biphenyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2oxoethyl) -5-(pyrimidin-5-yl)-1 H-indazol-3-carboxamide (2).

2-(3-carbamoyl-5-(nirimidin-5-yl)-1H-indazol-1-yl)acetic acid (45 mg, 1 eq.) from the previous step was dissolved in DMF (10 ml) and DIEA (0 , 12 ml, 5 eq.) followed by the addition of (2S,4R)-N-(3-chloro-(2S,4R)-N-(6-chloro-niridin-2-yl)-4-fluoro-pyrrolidin-2-carboxamide hydrochloride (50 mg, 1 eq.) at 5° C. HATU (118 mg, 2.1 eq.) was then slowly added at the same temperature and the reaction mixture was stirred for 3 hours at RT. The reaction mixture was then added to water (25 ml + 5 g solid NaCl) and extracted with DCM (2x15 ml).The organic layer was washed successively with aqueous NaHCO ₃ (10 ml), water (10 ml) and saline (10 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure.The remaining residue was purified by flash column chromatography (eluted with DCM/MeOH) to give ^2.1H NMR (400 MHz, DMSOd6, 300 K): (main rotamer) δ 2.11-2.29 (m , 1H), 2.51-2.62 (m, 1H), 3.89-4.08 (m, 1H), 4.18-4.30 (m, 1H), 4.76 (t, 1H), 5.48-5.76 (m, 3H), 7.06 (t , 1H), 7.23 (t, J=8.0 Hz, 1H), 7.37-7.48 (m, 4H), 7.57 (m, 1H), 7.72-7.88 (m, 2H), 7.86 (t, 1H), 8.47 ( s, br, 1H), 9.15 (s, 2H), 9.21 (s, 1H), 9.99 (s, 1H); ¹⁹ F NMR (376 MHz, DMSO-d6, 300K): (main) δ -126.69, -175.86. LC (method A): t _R =1.82 min. LC/MS (EI) m/z: [M+H] ^4,616 .

- 56 043505

Scheme 6

Step 1: tert-butyl-2-(3-carbamoyl-5-(2-pyrrolidin-1-yl)pyrimidin-5-yl)-1H-indazol-1yl)acetate.

Mixture of tert-butyl-2-(5-bromo-3-carbamoyl-1H-indazol-1-yl)acetate (316 mg), 2-(pyrrolidin-1-yl)-5(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (271 mg), cesium carbonate (350 mg, 2 equiv), DMF (10 ml) and water (1.5 ml) were purged with argon in a pressure vessel at for 5 minutes Tetrakis(triphenylphosphine)palladium(0) (57 mg) was then added under argon and the pressure vessel was sealed and heated at 100° C. overnight. The reaction mixture was cooled to room temperature. and the solvent was removed under reduced pressure. The crude product was used directly in the next stage of the synthesis.

Step 2: 2-(3-carbamoyl-5-(2-pyrrolidin-1-yl)pyrimidin-5-yl)-1H-indazol-1-yl)acetic acid.

Take tert-butyl-2-(3-carbamoyl-5-(2-pyrrolidin-1 -yl)pyrimidin-5-yl)-1 H-indazol-1-yl)acetate (crude from the above reaction) in 4N. HCl in dioxane (5 ml) and the resulting reaction mixture was stirred at room temperature. for 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Step 3: 1-(2-((2S,4R)-2-((2'-chloro-2-fluoro-[1,1'-biphenyl)carbamoyl)-4-fluoronirrolidin-1-yl)-2oxoethyl) -5-(2-pyrrolidin-1-yl)-1 H-indazol-3-carboxamide (10).

2-(3-carbamoyl-5-(2-pyrrolidin-1-yl)pyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (110 mg, 1 eq.) was dissolved in DMF (10 ml) and DIEA (0.3 ml) was added followed by (2S,4R)-N-(3-chloro-(2S,4R)-N-(6-chloropyridin-2-yl)-4-fluoropyrrolidin-2- carboxamide (110 mg, 1 eq.) at 5° C. Then, at the same temperature, HATU (118 mg,) was slowly added and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was then added to water (50 ml + 10 g solid NaCl) and extracted with DCM (2x20 ml).The organic layer was washed successively with aqueous NaHCO ₃ (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure.The remaining residue was purified by flash column chromatography (eluted with DCM/MeOH) to give ^10.1H NMR (400 MHz, DMSO-d6, 300 K): (main rotamer) δ 1.96 (m, 4H), 2.07-2.25 (m, 1H), 2.49-2.62 (m, 1H), 3.53 (m, 4H), 3.78-3.92 (m, 1H), 4.18-4.27 (m, 1H), 4.66 (t, 1H), 5.45-5.51 (m, 1H), 5.58-5.69 (m, 2H), 7.04 (t, 1H), 7.21 (t, J=8.0 Hz, 1H), 7.32-7.48 (m, 4H), 7.53-7.69 ( m, 4H), 7.95 (m, 1H), 8.24 (s, 1H), 9.97 (s, 1H); ¹⁹ F NMR (376 MHz, DMSO-d6, 300K): (main rotamer) δ -126.70, -175.88. LC (method A): t _R =2.33 min. LC/MS (EI) m/z: [M+H] ⁺ 685.

- 57 043505

Scheme 7

Step 1: tert-butyl-2-(3-carbamoyl-5-(6-fluoropyridin-3-yl)-III-indazol-1-yl) acetate.

A mixture of tert-butyl-2-(5-bromo-3-carbamoyl-1H-indazol-1-yl)acetate (211 mg), 6-fluoropyridin-3ylboronic acid (135 mg), cesium carbonate (350 mg, 2 eq. ), DMF (9 ml) and water (1.0 ml) were purged with argon in a pressure vessel for 5 min. Tetrakis(triphenylphosphine)palladium(0) (50 mg) was then added under argon and the pressure vessel was sealed and heated at 100° C. overnight. The reaction mixture was cooled to room temperature. and the solvent was removed under reduced pressure. The crude product was used directly in the next stage of synthesis.

Step 2: 2-(3-carbamoyl-5-(6-fluoropyridin-3-yl)-1H-indazol-1-yl)acetic acid.

Take tert-butyl-2-(3-carbamoyl-5-(6-fluoropyridin-3-yl)-1H-indazol-1-yl)acetate (crude from the above reaction) in 4N. HCl in dioxane (5 ml) and the resulting reaction mixture was stirred at room temperature. for 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Step 3: 1 -(2-((2S,4R)-2-((2'-chloro-2-fluoro-[1,1'-biphenyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2oxoethyl) -5 -(6-fluoropyridin-3-yl)-1 H-indazol-3-carboxamide (12).

2-(3-carbamoyl-5-(6-fluoropyridin-3-yl)-1H-indazol-1-yl)acetic acid (110 mg, 1 eq.) was dissolved in DMF (10 ml) and DIEA (0. 3 ml) followed by the addition of (2S,4R)-N-(3chloro-(2S,4R)-N-(6-chloropyridin-2-yl)-4-fluoropyrrolidin-2-carboxamide hydrochloride (110 mg, 1 eq. ) at 5° C. HATU (118 mg,) was then slowly added at the same temperature and the reaction mixture was stirred for 3 hours at RT. The reaction mixture was then added to water (50 ml + 10 g solid NaCl) and extracted with using DCM (2x20 ml).The organic layer was washed successively with aqueous NaHCO ₃ (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified with using flash column chromatography (eluted with DCM/MeOH) to obtain 12.1H NMR (400 MHz, DMSO- _d6 , 300 K): (main rotamer) δ 2.10-2.32 (m, 1H), 2.49-2.65 (m, 1H) , 3.88-4.06(m, 1H), 4.18-4.29 (m, 1H), 4.73 (t, 1H), 5.955.74 (m, 3H), 7.05 (t, 1H), 7.21 (t, J=8.0 Hz , 1H), 7.31-7.48 (m, 5H), 7.46 (m, 1H), 8.27 (m, 1H), 8.39 (s, 1H), 8.55 (s, 1H), 9.98 (s, 1H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ , 300K): (main rotamer) δ -125.25, -175.87. LC (method A): tR=2.43 min. LC/MS (EI) m/z: [M+H] ⁺ 633.

Scheme 8

Step 1: (1R,3S,5R)-tert-butyl-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2carboxylate.

To an ice-cooled solution of (1R,3S,5R)-tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-2carboxylic acid (1.5 g) in DCM (20 ml) was added dropwise with stirring 1 -χλορ- Ν,Ν,2

- 58 043505 trimethyl-1-propenylamine (998 mg, 1.1 eq.). Stirring was continued for 3 hours at this temperature and then solid 6-bromopyridin-2-amine (1.3 g, 1.1 eq) was added followed by DIEA (3.34 ml, 3 eq). The cooling bath was removed and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then added to water (20 ml) and extracted with DCM (2x25 ml). The organic layer was washed successively with aqueous NaHCO ₃ (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (eluted with hexanes/EtOAc) to give (1R,3S,5R)-tert-butyl-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1. 0]hexane-2-carboxylate.

Step 2: (1R,3S,5R)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3carboxamide hydrochloride.

Take (1R,3S,5R)-tert-butyl-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2carboxylate (500 mg) in 4N. HCl in dioxane (25 ml) and the resulting reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the remaining residue was used directly in the next step of the synthesis.

Scheme 9

MpPhahGejCttj

DMF-Η,Ο (9:1) stage 1

N HCI e dioisane

Step 1: tert-butyl-2-(3-carbamoyl-5-(pyrimidin-5-yl)-1H-indazol-1-yl) acetate.

Blend of tert-butyl 2-(5-bromo-3-carbamoyl-1H-indazol-1-yl)acetate (211 mg), pyrimidin-5ylboronic acid (135 mg), cesium carbonate (350 mg, 2 eq), DMF (9 ml) and water (1.0 ml) were purged with argon in a pressure vessel for 5 min. Tetrakis(triphenylphosphine)palladium(0) (50 mg) was then added under argon and the pressure vessel was sealed and heated at 100°C overnight. The reaction mixture was cooled to room temperature. and the solvent was removed under reduced pressure. The crude product was used directly in the next stage of synthesis.

Step 2: 2-(3-carbamoyl-5-(pyrimidin-5-yl)-1H-indazol-1-yl)acetic acid.

Take tert-butyl-2-(3-carbamoyl-5-(pyrimidin-5-yl)-1H-indazol-1-yl)acetate (crude from the above reaction) in 4N. HCl in dioxane (5 ml) and the resulting reaction mixture was stirred at room temperature. for 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Step 3: 1-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabiclo[3.1.0]hexan-2-yl-2oxoethyl)5- (pyrimidin-5-yl)-1H-indazol-3-carboxamide (4).

2-(3-carbamoyl-5-(pyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (110 mg) obtained in the previous step was dissolved in DMF (20 ml) and DIEA (0. 3 ml) followed by the addition of (1R,3S,5R)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride (126 mg) at 5°C. HATU (350 mg) was then added slowly at the same temperature and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was then added to water (50 ml+10 g solid NaCl) and extracted with DCM (2x20 ml). The organic layer was washed successively with aqueous NaHCO ₃ (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (eluted with DCM/MeOH) to give ^4.1H NMR (400 MHz, DMSO- _d6 , 300 K): (main rotamer) δ 0.75 (m, 1H), 1.02 (m, 1H ), 1.85 (m, 1H), 2.16-2.35 (m, 2H), 3.80 (m, 1H), 4.42 (m, 1H), 5.54 (d, 1H), 5.86 (d, 1H), 7.32 (t, 1H), 7.48 (br s, 1H), 7.68-7.88 (m, 4H), 8.03 (d, 1H), 8.46 (s, 1H), 9.23 (s, 2H),

- 59 043505

10.76 (s, 1H); LC (method A): t _R =1.42 min. LC/MS (EI) m/z: [M+H]+ 561.

Scheme 10

Step 1: tert-butyl-2-(3-carbamoyl-5-(2-pyrrolidin-1-yl)pyrimidin-5-yl)-III-indazol-1yl)acetate.

Mixture of tert-butyl-2-(5-bromo-3-carbamoyl-1H-indazol-1-yl)acetate (316 mg), 2-(pyrrolidin-1-yl)-5(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (271 mg), cesium carbonate (350 mg), DMF (10 ml) and water (1.5 ml) were purged with argon in a pressure vessel for 5 min . Tetrakis(triphenylphosphine)palladium(0) (57 mg) was then added under argon and the pressure vessel was sealed and heated at 100° C. overnight. The reaction mixture was cooled to room temperature. and the solvent was removed under reduced pressure. The crude product was used directly in the next stage of synthesis.

Step 2: 2-(3-carbamoyl-5-(2-pyrrolidin-1-yl)pyrimidin-5-yl)-1H-indazol-1-yl)acetic acid.

Take tert-butyl-2-(3-carbamoyl-5-(2-pyrrolidin-1-yl)pyrimidin-5-yl)-1H-indazol-1-yl)acetate (crude from the above reaction) in 4N. HCl in dioxane (5 ml) and the resulting reaction mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next step of the synthesis.

Step 3: 1-(2-((1R,3S,5R)-3-((6-bromoniridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl-2oxoethyl)5- ((2-nirrolidin-1-yl)pyrimidin-5-yl)-1H-indazol-3-carboxamide (11).

2-(3-carbamoyl-5-(2-pyrrolidin-1-yl)nirimidin-5-yl)-1H-indazol-1-yl)acetic acid (131 mg) obtained in the previous step was dissolved in DMF (20 ml) and DIEA (0.25 ml) was added followed by (1R,3S,5R)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3carboxamide hydrochloride (110 mg) at 5°C. HATU (240 mg) was then added slowly at the same temperature and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was then added to water (50 ml + 10 g solid NaCl) and extracted with DCM (2x20 ml). The organic layer was washed successively with aqueous NaHCO ₃ (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (eluted with DCM/MeOH) to give 11. Ή NMR (400 MHz, DMSO-d6, 300 K): (main rotamer) δ 0.74 (m, 1H), 1.01 (m, 1H ), 1.25 (m, 1H), 1.86-1.98 (m, 5H), 2.13-2.38 (m, 2H), 3.56 (m, 4H), 3.80 (m, 1H), 4.42 (m, 1H), 5.51 ( d, 1H), 5.82 (d, 1H), 7.19 (d, J=6.8 Hz, 1H), 7.40 (br s, 1H), 7.64-7.72 (m, 4H), 8.01 (d, 1H), 8.27 ( s, 1H), 8.66 (s, 2H), 10.75 (s, 1H); LC (method A): t _R =1.82 min. LC/MS (EI) m/z: [M+H] ⁺ 630.

Scheme 11

(2 S,4R)-1-tert-butyl-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1 Step 1:

- 60 043505 carboxylate.

1-Chloro-N,N,2trimethyl- 1-propenylamine (998 mg, 1.1 eq.). Stirring was continued for 3 hours at this temperature and then solid 6-bromopyridin-2-amine (1.3 g, 1.1 eq) was added followed by DIEA (3.34 ml, 3 eq). The cooling bath was removed and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then added to water (20 ml) and extracted with DCM (2x25 ml). The organic layer was washed successively with aqueous NaHCO ₃ (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (eluted with hexanes/EtOAc) to give (2S,4R)-tert-butyl-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate.

Step 2: (2S,4R)-N-(6-Bromopyridin-2-yl)-4-fluoropyrrolidin-2-carboxamide hydrochloride.

Take (2S,4R)-1-tert-butyl-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (1.5 g) in 4N. HCl in dioxane (25 ml) and the resulting reaction mixture was stirred at room temperature. for 3 hours. The solvent was removed under reduced pressure and the remaining residue was used directly in the next stage of the synthesis.

Scheme 12

Step 1: tert-butyl-2-(3-carbamoyl-5-(4-morpholinophenyl)-1H-indazol-1-yl)acetate.

A mixture of tert-butyl-2-(5-bromo-3-carbamoyl-1H-indazol-1-yl)acetate (316 mg), (4morpholinophenyl)boronic acid (224 mg), cesium carbonate (585 mg, 2 eq), DMF (20 ml) and water (2 ml) were purged with argon in a pressure vessel for 5 min. Tetrakis(triphenylphosphine)palladium(0) (45 mg) was then added under argon and the pressure vessel was sealed and heated at 100° C. overnight. The reaction mixture was cooled to room temperature. and the solvent was removed under reduced pressure. The crude product was used directly in the next stage of the synthesis.

Step 2: 2-(3-carbamoyl-5-(4-morpholinophenyl)-1H-indazol-1-yl)acetic acid.

Take tert-butyl-2-(3-carbamoyl-5-(4-morpholinophenyl)-III-indazol-1-yl) acetate (crude from the above reaction) in 4N. HCl in dioxane (5 ml) and the resulting reaction mixture was stirred at room temperature. for 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Step 3: 1 -(2-((2S,4R)-2-((6-Bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidin-1 -yl)-2-oxoethyl)5-(4-morpholinophenyl) -1H-inαzole-3-carboxamide (3).

2-(3-carbamoyl-5-(4-morpholinophenyl)-III-indazol-1-yl)acetic acid (177 mg, 1 eq.) from the previous step was dissolved in DMF (10 ml) and DIEA (0.25 ml) followed by the addition of (2S,4R)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidin-2-carboxamide hydrochloride (118 mg, 1 eq.) at 5°C. HATU (248 mg) was then added slowly at the same temperature and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was then added to water (50 ml + 10 g solid NaCl) and extracted with DCM (2x20 ml). The organic layer was washed successively with aqueous NaHCO ₃ (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (eluted with DCM/MeOH) to give ^3.1H NMR (400 MHz, DMSO- _d6 , 300 K): (main rotamer) δ 2.07-2.22 (m, 1H), 2.49-2.61 (m, 1H), 3.12-3.18 (m, 4H), 3.73-3.78 (m, 4H), 3.86-4.09 (m, 1H),

- 61 043505

4.13-4.25 (m, 1H), 4.66 (t, J=8.4 Hz, 1H), 5.42-5.48 (m, 1H), 5.58-5.70 (m, 2H), 7.04 (t, J=6.4 Hz, 1H) , 7.31 (t,

J=8.0 Hz, 1H), 7.35-7.52 (m, 1H), 7.50-7.58 (d, J=8.4 Hz, 2H), 7.63-7.75 (m, 4H), 8.02 (d, J=8 Hz, 1H ), 8.32 (s,

1H), 10.99 (s, 1H); ^19F NMR (376 MHz, DMSO- _d6 , 300K): (main) δ -175.70. LC (method A): t _R =1.82 min.

LC/MS (EI) m/z: [M+H] ⁺ 650.

Stage

Scheme 13

(1 R,3S,5R)-tert-butyl-3-((2'-chloro-2-fluoro-[1,1'-biphenyl]-3 -yl)carbamoyl)-21:

azabicyclo[3.1.0]hexane-2-carboxylate.

To an ice-cooled solution of (1R,3S,5R)-tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-2carboxylic acid (1.13 g) in DCM (20 ml), 1-χλορ- N,N,2trimethyl-1-propenylamine (731 mg, 1.1 eq.). Stirring was continued for 3 hours at this temperature and then solid 2'-chloro-2-fluoro-[1,1'-biphenyl]-3-amine hydrochloride (1.3 g, 1 eq) was added followed by DIEA ( 2.45 ml). The cooling bath was removed and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then added to water (20 ml) and extracted with DCM (2x25 ml). The organic layer was washed successively with aqueous NaHCO ₃ (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (eluted with hexanes/EtOAc) to give (1R,3S,5R)-tert-butyl-3-((2'-chloro-2-fluoro-[1,1'-biphenyl] -3yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate.

Stage

2:

(1R,3S,5R)-N-(2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)-2azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride.

We took (1R,3S,5R)-tert-butyl-3-((2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)carbamoyl)2azabicyclo[3.1.0]hexane-2 -carboxylate (700 mg) in 4N. HCl in dioxane (25 ml) and the resulting reaction mixture was stirred at room temperature. for 3 hours. The solvent was removed under reduced pressure and the remaining residue was used directly in the next stage of the synthesis.

Scheme 14 about ^:

РсЦРРШЧ.СагССН

DMF-H _; Ora:1i

Step 1: tert-butyl-2-(3-carbamoyl-5-(pyrimidin-5-yl)-1H-indazol-1-yl) acetate.

A mixture of tert-butyl-2-(5-bromo-3-carbamoyl-1H-indazol-1-yl)acetate (211 mg), pyrimidin-5ylboronic acid (82 mg), cesium carbonate (391 mg, 2 eq.), DMF (9 ml) and water (1.0 ml) were purged with argon in a pressure vessel for 5 min. Tetrakis(triphenylphosphine)palladium(0) (40 mg) was then added under argon and the pressure vessel was sealed and heated at 100° C. overnight. The reaction mixture was cooled to room temperature. and the solvent was removed under reduced pressure. The crude product was used directly in the next stage of synthesis.

Step 2: 2-(3-carbamoyl-5-(pyrimudin-5-yl)-1H-indazol-1-yl)acetic acid.

Take tert-butyl-2-(3-carbamoyl-5-(pyrimidin-5-yl)-1H-indazol-1-yl)acetate (crude from the above reaction) in 4N. HCl in dioxane (5 ml) and the resulting reaction mixture was stirred at room temperature. for 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Step 3: 1 -(2-(( 1 R,3S,5R)-3-((2'-chloro-2-fluoro-[1,1'-biphenyl]-3 -yl)carbamoyl)azabicyclo[3.1. 0]hexan-2-yl)-2-oxoethyl)-5-(pyrumidin-5-yl)-1H-undazol-3-carboxamide (6).

2-(3-carbamoyl-5-(pyrumidin-5-yl)-1H-undazol-1-yl)acetic acid (131 mg, 1 eq.) from the previous step was dissolved in DMF (10 ml) and DIEA (0 , 33 ml, 5 eq.) followed by the addition of (1R,3S,5R)-N-(2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)2-αsαbuticlo[3.1] hydrochloride .0]heksαn-3carboxamide (131 mg, 1 eq.) at 5°C. HATU (350 mg, 2.1 eq.) was then added slowly at the same temperature and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was then added to water (25 ml + 5 g solid NaCl) and extracted with DCM (2x15 ml). The organic layer was washed successively with aqueous NaHCO ₃ (10 ml), water (10 ml) and brine (10 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (eluted with DCM/MeOH) to give 6. Ή NMR (400 MHz, DMSO-d ₆ , 300 K): (main rotamer) δ 0.73 (m 1H), 1.07 (m, 1H ), 1.26 (m, 1H), 1.90 (m, 1H), 2.28-2.35 (m, 2H), 3.78-3.83 (m, 1H), 4.54 (m, 1H), 5.52 (d, 1H), 5.84 ( d, 1H), 7.07 (t, J=6.4 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H), 7.35-7.58 (m, 4H), 7.55 (d, 1H), 7.72-7.84 (m , 4H), 8.47(s, 1H), 9.72 (s, 1H); ^19F NMR (376 MHz, DMSO- _d6 , 300K): (main) δ -126.54. LC (method A): t _R =1.96 min. LC/MS (EI)m/z: [M+H] ⁺ 610.

Scheme 15

Step 1: 5-chloro-3-iodo-1H-pyrazolo[3,4]pyridine.

To a solution of 5-chloro-1H-pyrazolo[3,4-c]pyrudine (15 g, 1 eq.) in DMF (150 ml) was added iodine (37.2 g, 1.5 eq.) and potassium hydroxide (13 .7 g, 2.5 eq.) at 0°C. The reaction mixture was stirred at room temperature. for 12 hours and then diluted with 10% aqueous sodium thiosulfate (250 ml) and extracted with EtOAc. The combined organic extracts were washed with saline and then dried. The resulting solid (15 g) was suspended with MTBE, filtered and dried.

Step 2: tert-butyl-2-(5-chloro-3-iodo-1H-pyrazolo[3,4]pyridin-1-yl)acetate.

To a mixture of 5-chloro-3-iodo-1H-pyrazolo[3,4]pyridine (14 g, 1 eq.) and potassium carbonate (8.3 g, 1.2 eq.) in DMF (140 ml) was added drops tert-butyl bromoacetate (8.9 ml, 1.2 eq.) at room temperature. and the resulting mixture was stirred at 50°C for 3 hours. The reaction mixture was then poured into water and extracted with EtOAc; the combined organic extracts were concentrated under reduced pressure. The resulting material was taken to the next stage without additional purification.

Step 3: tert-butyl-2-(5-chloro-3-cyano-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate.

A mixture of tert-butyl-2-(5-chloro-3-iodo-1H-pyrazolo[3,4]pyridin-1-yl)acetate (12.5 g, 1 eq.), Zn(CN)2 (4, 5 g, 1.2 eq.), Pd(dppf)Cl ₂ (2.6 g, 0.1 eq.), Pd ₂ (dba) ₃ (2.9 g, 0.1 eq.), water ( 25 ml) and DMF (125 ml) were stirred at 100°C for 5 hours under nitrogen atmosphere. The reaction mixture was diluted with EtOAc and then washed successively with water, saturated aqueous NaHCO ₃ and brine. The combined organic layer was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound.

Step 4: tert-butyl-2-(3-carbamoyl-5-chloro-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate.

A mixture of tert-butyl-2-(5-chloro-3-cyano-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate (5.7 g, 1 eq.), acetaldoxime (2.3 g , 2 eq.), Pd(OAc) ₂ (0.22 g, 0.05 eq.) and PPh ₃ (0.54 g, 0.1 eq.) in aqueous ethanol (143 ml, H2O/EtOH (29 ml/114 ml) was heated to 90°C for 3 hours under nitrogen atmosphere. The reaction mixture was filtered through Celite and the solvent was removed under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane/EtOAc) with obtaining the title compound (3.5 g).

Scheme 16

Step 1: 2-(3-carbamoyl-5-(pyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetic acid.

Mixture of tert-butyl-2-(3-carbamoyl-5-chloro-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate (311 mg, 1 mmol), pyrimidin-5-ylboronic acid (248 mg , 2 mmol), K3PO4 (634 mg, 3 mmol), dioxane (9 ml) and water (1 ml) were degassed and replenished with argon three times. Pd(PPh ₃ ) ₄ (58 mg, 0.05 mmol) was added to this mixture under argon and the reaction mixture was heated in an oil bath at 85 °C overnight. Additional Pd(PPh ₃ ) ₄ (58 mg, 0.05 mmol) was added to the solution and the reaction mixture was kept at 85°C for an additional 24 hours. The reaction mixture was cooled to room temperature. and volatiles were removed under reduced pressure. The remaining residue was acidified with 10% aqueous citric acid (10 ml) and extracted with ethyl acetate (20 ml). The organic layer was discarded and the aqueous phase was evaporated to dryness. The remaining solid was loaded onto a bed of silica gel and washed with methanol. The methanol solution was concentrated and evaporated together with toluene. The resulting solid was dried under high vacuum and used in the next step without further purification.

Step 2: 1-(2-((2S,4R)-2-((2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidine-1- yl)2-oxoethyl)-5-(pyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (19).

To a mixture of 2-(3-carbamoyl-5-(pyrimidin-5-yl)-III-pyrazolo[3,4-c]pyridin-1-yl)acetic acid (77 mg, 0.26 mmol), HATU (120 mg, 0.32 mmol, 1.2 eq.), hydrochloride (2S,4R)-N-(2'-chloro-2-fluoro-[1, 1'biphenyl]-3-yl)-4-fluoropyrrolidin- 2-carboxamide (96 mg, 0.26 mmol) and DMF (2.5 ml) were added to DIEA (0.15 ml, 0.86 mmol) at RT. The reaction mixture was stirred for 30 min at room temperature. and then the volatiles were removed under reduced pressure. The remaining residue was subjected to preparative HPLC to obtain 40.9 mg of the title product. 1H NMR (400 MHz, DMSO-d ₆ , 300 K): (main rotamer) δ 2.17-2.25 (m, 1H), 2.49-2.57 (m, 1H), 3.86-3.99 (m, 1H), 4.13-4.22 (m, 1H), 4.73 (t, J=8.4 Hz, 1H), 5.57-5.61 (m, 1H), 5.65-5.84 (m, 2H), 6.99 (t, J=6.4 Hz, 1H), 7.14 ( t, J=8.0 Hz, 1H), 7.28-7.42 (m, 4H), 7.507.58 (m, 1H), 7.83-7.92 (m, 2H), 8.58 (s, 1H), 9.15 (s, 1H) , 9.23 (s, 1H), 9.38 (s, 2H), 9.95 (s, 1H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ , 300K): (main rotamer) δ -126.77, -175.85. LC (method A): t _R =2.47 min. LC/MS (EI) m/z: [M+H]+ 617.

Scheme 17

Step 1: tert-butyl 2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-1H-indol-1-yl) acetate.

Mixture of tert-butyl-2-(3-acetyl-5-bromo-1H-indol-1-yl)acetate (351 mg, 1 eq.), (2methoxypyrimidin-5-yl)boronic acid (230 mg, 1.5 eq.), cesium carbonate (650 mg, 2 eq.), DMF (15

- 64 043505 ml) and water (1.5 ml) were purged with argon in a pressure vessel for 5 min. Tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.05 eq.) was then added under argon and the pressure vessel was sealed and heated at 100° C. overnight. The reaction mixture was cooled to room temperature. and the solvent was removed under reduced pressure. The crude product was used directly in the next stage of the synthesis.

Step 2: 2-(3-Acetyl-5-(2-methoxypyrimidin-5-yl)-1H-indol-1-yl)acetic acid.

Take crude tert-butyl-2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-1H-indol-1-yl) acetate (top) in 4N. HCl in dioxane (20 ml) and the resulting reaction mixture was stirred at room temperature. for 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Step 3: (2S,4R)-1-(2-(3-Acetyl-5-(2-methoxypyrimidin-5-yl)-1H-indol-1-yl)acetyl)-N-(2'-chloro2- fluoro-[1,1'-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamide (27).

2-(3-Acetyl-5-(2-methoxypyrimidin-5-yl)-1H-indol-1-yl)acetic acid (100 mg, 1 eq.) from the previous step was dissolved in DMF (10 ml) and added to DIEA (0.269 ml, 5 eq.) followed by the addition of (2S,4R)-N-(3-chloro-(2S,4R)-N-(6-chloropyridin-2-yl)-4-fluoropyrrolidine-2carboxamide hydrochloride ( 111 mg, 1 eq.) at 5° C. HATU (263 mg, 2.1 eq.) was then added slowly at the same temperature and the reaction mixture was stirred for 3 hours at RT. The reaction mixture was then added to water ( 50 ml + 10 g NaCl) and extracted with DCM (2x25 ml).The organic layer was washed successively with aqueous NaHCO ₃ (20 ml), water (20 ml) and saline (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure.The remaining residue was purified by flash column chromatography (eluted with DCM/MeOH) to give ^27.1H NMR (400 MHz, DMSO-d6, 300 K): (main rotamer) δ 2.13-2.3 (m , 1H), 2.45 (s, 3H), 2.68-2.70 (m, 1H), 3.95-4.05 (m, 4H), 4.16-4.24 (m, 1H), 4.78 (t, J=8 Hz, 1H), 5.28 (d, J=20 Hz, 1H), 5.45 (d, J=20 Hz, 1H), 5.50-5.63 (m, 1H), 7.04-7.08 (m, 1H), 7.20-7.24 (m, 1H) , 7.37-7.61 (m, 7H), 7.75-7.78 (m, 1H), 7.94-7.98 (m, 1H), 8.31 (s, 1H), 8.88 (s, 1H), 8.97 (s 1H); ¹⁹ F NMR (376 MHz, DMSO-d6, 300 K): (main rotamer) δ -126.64, -175.79. LC (method A): t _R =2.16 min. LC/MS (EI) m/z: [M+H] ⁺ 644.

Scheme 18

Synthesis of (2S,4R)-1-(2-(3-acetyl-5-(4-acetylpiperazin-1-yl)-1H-indol-1-yl)acetyl)-N-(2'-chloro-2- fluoro[1,1'-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamide (16).

Step 1: 1-(5-bromo-1H-indol-3-yl)ethanone.

1-(5-bromo-1H-indol-3-yl)ethanone was prepared from 5-bromoindole according to the procedure described by MacKay et al. (MacKay, J. A.; Bishop, R.; Rawal, V. H. Org. Lett. 2005, 7, 3421-3424).

Step 2: tert-butyl-2-(3-acetyl-5-bromo-1H-indol-1-yl) acetate.

- 65 043505

A mixture of 1-(5-bromo-1H-indol-3-yl)ethanone (3.9 g, 16.4 mmol), tert-butyl bromoacetate (2.63 ml (18.02 mmol) and potassium carbonate (2.50 g, 18.02 mmol) in anhydrous acetonitrile (80 ml) was refluxed for 5 hours. The reaction mixture was then cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in a 1:1 mixture of DCM and water ( 100 ml:100 ml).The two layers were separated and the organic layer was washed with water (2x100 ml). Finally, the organic layer was dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was stirred with 50 ml of heptane for 30 minutes, cooled in an ice bath and the filtered solid, washed with cold heptane (10 ml).The solid was dried under high vacuum to give tert-butyl-2-(3-acetyl-5-bromo-1H-indol-1-yl)acetate (5.6 g ).

Step 3: tert-butyl-4-(3-acetyl-1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-5-yl)piperazine-1carboxylate.

A mixture of tert-butyl-2-(3-acetyl-5-bromo-1H-indol-1-yl)acetate (379 mg), tert-butylpiperazine-1carboxylate (223 mg, 1.2 eq.), cesium carbonate (489 mg, 1.4 eq.), (S)-(-)-2,2-bis(biphenylphosphino)-1,1binaphthyl (40 mg) and toluene (8 ml) were purged with argon for 5 min. Tris(dibenzylideneacetone)dipalladium(0) (40 mg) was then added under argon and the reaction mixture was heated at 100°C overnight. The reaction mixture was cooled to room temperature. and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (EtOAc gradient in hexanes) to give tert-butyl-4-(3-acetyl-1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-5-yl) piperazine-1carboxylate (89 mg).

Step 4: TFA salt of tert-butyl-2-(3-acetyl-5-(piperazin-1-yl)-1H-indol-1-yl)acetate.

Tert-butyl-4-(3-acetyl-1-(2-(tert-butoxy)-oxoethyl-1H-indol-5-yl)piperazine-1-carboxylate (65 mg) was dissolved in 5% TFA (0.5 ml) in DCM (10 ml) at 0-5°C and the resulting reaction mixture was stirred at 0-5°C for 24 hours. The solvent was then removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Step 5: tert-butyl-2-(3-acetyl-5-(4-acetylpiperazin-1-yl)-1H-indol-1-yl)acetate.

The TFA salt of tert-butyl-2-(3-acetyl-5-(piperazin-1-yl)-1H-indol-1-yl)acetate from step 4 was dissolved in DCM (4 ml) and DIEA (0.14 ml) was added , excess) followed by the addition of AcCl (0.02 ml, 1 eq.) at 0-5°C. After stirring for 10 min, the reaction mixture was diluted with EtOAc (10 ml) and water (4 ml). The EtOAc layer was separated, washed with brine (15 ml), dried (Na2SO4) and evaporated to dryness under reduced pressure. The remaining material was used directly in the next step.

Step 6: 2-(3-acetyl-5-(4-acetylpiperazin-1-yl)-1H-indol-1-yl)acetic acid.

tert-Butyl-2-(3-acetyl-5-(4-acetylpiperazin-1-yl)-1H-indol-1-yl)acetate from the previous step was dissolved in DCM (5 ml) and TFA (1 ml) was added. The reaction mixture was stirred overnight at room temperature. The solvent was then removed under reduced pressure and the remaining material was used directly in the next synthesis step.

Step 7: (2S,4R)-1 -(2-(3-acetyl-5-(4-acetylpiperazin-1 -yl)-1H-indol-1 -yl)acetyl)-N-(2'-chloro- 2fluoro-[1,1'-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamide.

To a solution of 2-(3-acetyl-5-(4-acetylpiperazin-1-yl)-1H-indol-1-yl)acetic acid from step 6 in DMF (5 ml) was added DIEA (0.13 ml, 3 eq. ) and then (2S,4R)-N-(3-chloro-(2S,4R)-N-(6chloropyridin-2-yl)-4-fluoropyrrolidin-2-carboxamide hydrochloride (108 mg, 1.1 eq.) HATU (120 mg, 1.2 eq.) was then added slowly and the reaction mixture was stirred for 18 h at RT. The reaction mixture was then added to water (10 ml) and extracted with EtOAc (2x15 ml).Organic layer washed successively with aqueous NaHCO ₃ (10 ml), water (10 ml) and brine (10 ml), then dried over Na2SO4 and concentrated under reduced pressure.The remaining residue was purified using flash column chromatography (eluted with DCM/CH3OH) with obtaining the title compound: 1H NMR (400 MHz, DMSO- _d6 , 300 K): (main rotamer) δ 2.18 (s, 3H), 2.24-2.41 (m, 1H), 2.50 (s, 3H), 2.64 -2.78 (m, 1H), 3.08-3.19 (m, 4H), 3.69-3.80 (m, 4H), 3.91-4.09 (m, 1H), 4.16-4.27 (m, 1H), 4.78 (t, J= 8 Hz, 1H), 5.16 (d, J=17 Hz, 1H), 5.26 (d, J=17 Hz, 1H), 5.45-5.61 (m, 1H), 7.04-7.08 (m, 1H), 7.18- 7.25 (m, 1H), 7.38-7.47 (m, 4H), 7.51-7.56 (m, 1H), 7.86-7.90 (s, 1H), 7.93-7.98 (m, 1H), 8.12 (s, 1H); ¹⁹ F NMR (376 MHz, DMSO-d6, 300 K): (main rotamer) δ -128.56, -178.51. LC (method A): tR=2.30 min. LC/MS (EI) m/z: [M+H] ⁺ 664.

- 66 043505

Scheme 19 (2S,4R)-1 -(2-(3 -acetyl-5 -(4-methylsulfonylpiperazin-1 -yl)-1 H-indol-1 -yl)acetyl)-N-(2'-chloro- 2-fluoro[1,1'-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamide (33)

Step 1: tert-butyl-2-(3-acetyl-5-(4-(methylsulfonyl)piperazin-1-yl)-1H-indol-1-yl)acetate.

TFA salt of tert-butyl-2-(3-acetyl-5-(piperazin-1-yl)-1H-indol-1-yl)acetate (90 mg) was dissolved in DCM (4 ml). To this solution was added DIEA (0.14 ml) followed by the addition of methylsulfonyl chloride (0.06 ml) at 0-5°C. After stirring for 10 min, the reaction mixture was diluted with EtOAc (10 ml) and water (4 ml). The separated organic layer was washed with brine (15 ml), dried (Na ₂ SO ₄ ) and evaporated to dryness under reduced pressure. The remaining material was used directly in the next step.

Step 2: 2-(3-acetyl-5-(4-(methylsulfonyl)piperazin-1-yl)-1H-indol-1-yl)acetic acid.

tert-Butyl-2-(3-acetyl-5-(4-(methylsulfonyl)piperazin-1-yl)-1H-indol-1-yl)acetate was dissolved in DCM (5 ml) and TFA (1 ml) was added. The reaction mixture was stirred overnight at room temperature. and then the solvent was removed under reduced pressure. The remaining material was used directly in the next step.

Step 3: (2S,4R)-1 -(2-(3 -acetyl-5-(4-(methylsulfonyl)piperazin-1 -yl)-1 H-indol-1 -yl)acetyl)-N(2' -chloro-2-fluoro-[1,1'-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamide.

To a solution of 2-(3-acetyl-5-(4-(methylsulfonyl)piperazin-1-yl)-1H-indol-1-yl)acetic acid DMF (5 ml) was added DIEA (0.17 ml, 4 eq. ), followed by (2S,4R)-N-(3-chloro-(2S,4R)-N-(6chloropyridin-2-yl)-4-fluoropyrrolidin-2-carboxamide hydrochloride (102 mg, 1.1 eq. HATU (120 mg, 1.2 eq.) was then added slowly and the reaction mixture was stirred for 18 hours at RT. The reaction mixture was then added to water (10 ml) and extracted with EtOAc (2x15 ml).Organic the layer was washed successively with aqueous NaHCO ₃ (10 ml), water (10 ml) and brine (10 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure.The resulting residue was purified by HPLC to obtain the title compound ^.1H NMR (400 MHz, DMSO-d6, 300 K): (main rotamer) δ 2.18 (s, 3H), 2.27-2.42 (m, 1H), 2.50 (s, 3H), 2.67-2.80 (m, 1H), 2.98 (s, 3H), 3.52 (m, 8H), 3.95-4.29 (m, 2H), 4.78 (t, J=8 Hz, 1H), 5.21 (d, J=18 Hz, 1H), 5.35 (d, J=18 Hz, 1H), 5.42-5.63 (m, 1H), 7.04-7.08 (m, 1H), 7.14-7.20 (m, 1H), 7.22-7.29 (m, 1H), 7.30- 7.42 (m, 3H), 7.43-7.51 (m, 3H), 7.93-7.96 (m, 1H), 8.15 (s, 1H); ¹⁹ F NMR (376 MHz, DMSO-d6, 300 K): (main rotamer) δ -128.49, -178.41. LC (method A): tR=2.09 min. LC/MS (EI) m/z: [M+H]+ 698.

Scheme 20

Synthesis of (2S,4R)-1 -(2-(3 -acetyl-5-( 1 -acetyl-1,2,3,6-tetrahydropyridin-4-yl)-1 H-indol-1 -yl)acetyl) -N-(2'chloro-2-fluoro-[1,1'-biphenyl]-3-yl)-4-fluoropyrrolidin-2-carboxamide (28)

- 67 043505

Step 1: tert-butyl-2-(3-acetyl-5-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1yl)acetate.

Mixture of tert-butyl-2-(3-acetyl-5-bromo-1H-indol-1-yl)acetate (113 mg, 0.32 mmol), 1-(4-(4,4,5,5tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (80 mg, 0.32 mmol), cesium carbonate (209 mg, 0.64 mmol) and DMF ( 10 ml) was purged with argon in a pressure vessel for 5 min. Tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016 mmol) was then added under argon and the pressure vessel was sealed and heated at 90° C. overnight. The reaction mixture was cooled to room temperature. and the solvent was removed under reduced pressure. The remaining crude product was used directly in the next stage of the synthesis.

Step 2: 2-(3-acetyl-5-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-1 H-indol-1-yl)acetic acid.

We took tert-butyl-2-(3-acetyl-5-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-1 H-indol-1-yl)acetate in 4N. HCl in dioxane (10 ml) and the resulting reaction mixture was stirred at room temperature. for 4 hours. The solvent was then removed under reduced pressure, and the remaining material was used directly in the next stage of the synthesis.

Step 3: (2S,4R)-1 -(2-(3-acetyl-5-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1 yl)acetyl )-N-(2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamide.

The title compound was prepared from 2-(3-acetyl-5-(1-acetyl-1,2,3,6-tetrahydropyridin4-yl)-III-indol-1-yl)acetic acid (100 mg, 0.29 mmol) and (2S,4R)-N-(3-chloro-(2S,4R)N-(6-chloropyridin-2-yl)-4-fluoropyrrolidin-2-carboxamide hydrochloride (110 mg, 0.29 mmol) in a manner similar to that described above for (2S,4R)-1 -(2-(3-acetyl-5-(4-acetylpiperazin-1 -yl)-1 H-indol-1 -yl)acetyl)-N-(2 'chloro-2-fluoro-[1,1'-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamide ¹ H NMR (400 MHz, DMSO-d ₆ , 300

K): (main rotamer) δ 2.05-2.07 (s, 3H), δ 2.31-2.38 (m, 1H), 2.50 (s, 3H), 2.50-2.70 (m, 3H), 3.73-3.79 (m, 2H ), 4.01-4.31 (m, 4H), 4.85 (t, J=8.4 Hz, 1H), 5.28-5.50 (m, 2H), 5.64 (d, J=52.8 Hz, 1H), 6.18 (s, 1H) , 7.16 (t,

J=6.8 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.41-7.68 (m, 6H), 8.04 (t, J=7.6 Hz, 1H), 8.30 (d, J=8 Hz, 1H), 8.35 (s, 1H), 10.05 (s, 1H); 19F NMR (376 MHz, DMSO-de, 300 K): (main rotamer) δ -126.64, -175.81. LC (method A): t _R =2.07 min. LC/MS (EI) m/z: [M+H]+ 659.

Example 6 Non-limiting examples of compounds of formula I.

In table 1 shows illustrative compounds of formula I with characteristic data.

The analysis of Example 7 was used to determine the IC ₅₀ of the compounds. Other standard factor D inhibition assays are also available. Three *** are used to indicate compounds with an IC ₅₀ of less than 1 micromolar; two ** indicate a compound with an IC ₅₀ between 1 micromolar and 10 micromolar, and one * indicates a compound with an IC ₅₀ greater than 10 micromolar.

Table 1

Name IC50 RT min MS (Method (M+ A or 1) B) l-(2-((2S,4R)-2-(2'- *** 1.79(A) 604 chloro-2-fluorobiphenyl3 -ylcarbamoyl) -4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(1 H-pyrazol-4-yl)-1 Nindazol-3carboxamide

- 68 043505

l-(2-((2S,4R)-2-(2'-*** 1.82(A) 616 chloro-2-fluorobiphenyl3 -ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(pyrimidine - 5 -yl)-1Nindazol-3carboxamide l-(2-((2S,4R)-2-(6- *** 1.82(A) 650 bromopyridin-2ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)- 5-(4morpholinophenyl)1H-indazol-3carboxamide l-(2-((lR,3S,5R)-3-(6- *** 1.42(A) 561 bromopyridin-2ylcarbamoyl)-2azabicyclo[3.1.0]hexan -2-yl)-2-oxoethyl)5 -(pyrimidin-5 -yl)1H-ind azol-3 carboxamide

- 69 043505

l-(2-((2S,4R)-2-(6- *** 1.30(A) 567 bromopyridin-2ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(pyrimide in-5-yl) -1Nindazole-3carboxamide l-(2-((lR,3S,5R)-3-(2'- *** 1.96(A) 610 chloro-2-fluorobiphenyl3 -ylcarbamoyl)-2azabicyclo[3.1.0]hex an- 2-yl)-2-oxoethyl)5 -(pyrimidin-5-yl)1H-ind azol-3 carboxamide l-(2-((lR,3S,5R)-3-(2'- *** 2.15( A) 610 chloro-2-fluorobiphenyl3 -ylcarbamoyl)-2azabicyclo[3.1.0]hex an-2-yl)-2-oxoethyl)5 -(pyrimidin-2-yl)1H-ind azol-3 carboxamide

- 70 043505

l-(2-((lR,3S,5R)-3-(2- *** 1.74(A) 584 fluoro-3 (trifluoromethoxy)phenylcarbamoyl)-2azabicyclo[3.1.0]hexan-2-yl) -2-oxoethyl)5-(pyrimidin-5-yl)lH-ind azol-3 carboxamide

1-(2-((28.4K)-4-fluoro- *** 1.64(A) 590

2-(2-fluoro-3(trifluoromethoxy)phenylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(pyrimidin-5-yl)-1Nindazol-3carboxamide

1-(2-((28.4R)-2-(2'- *** 2.33 (A) 685 chloro-2-fluorobiphenyl3 -ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5-(2 (pyrrolidin-1 yl)pyrimidin-5-yl)1H-ind azol-3 carboxamide

- 71 043505

l-(2-((lR,3S,5R)-3-(6- *** 1.82(A) 630 bromopyridin-2ylcarbamoyl)-2azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl) 5 -(2-(pyrrolidin-1 yl)pyrimidin-5-yl)ΙΗ-ind azol-3 carboxamide l-(2-((2S,4R)-2-(2'- *** 2.43 (A) 633 chloro-2-fluorobiphenyl3 -ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5-(6fluoropyridin-3 -yl)1H-ind azol-3 carboxamide l-(2-((lR,3S,5R)- 3-(2'- *** 2.53 (A) 627 chloro-2-fluorobiphenyl3 -ylcarbamoyl)-2azabicyclo[3.1.0]hex an-2-yl)-2-oxoethyl)5 -(6-fluoropyr idin-3 yl)-1 H-ind azol-3 carboxamide

- 72 043505

(2S,4R)-l-(2-(3- *** 2.04(A) 565 acetyl-5 -(pyrimidine-

-yl)-1 H-ind ol-1 yl)acetyl)-M-(6bromopyridin-2-yl)-4fluoropyrrolidin-2carboxamide (lR,3S,5R)-2-(2-(3- *** 2.63 ( A) 608 acetyl-5 -(pyrimidine-

-yl)-1 H-ind ol-1 yl)acetyl)-M-(2'chloro-2-fluorobiphenyl3-yl)-2-azabicyclo[3.1.0]hex an-3 -carboxamide (2S,4R)- l-(2-(3- *** 2.30(A) 664 acetyl-5-(4acetylpiperazin-1 yl)-1 H-ind ol-1 yl)acetyl)-M-(2'chloro-2-fluorobiphenyl3- yl)-4fluoropyrrolidine-2carboxamide

- 73 043505

(lR,3S,5R)-2-(2-(3- *** 2.44(A) 559 acetyl-5 -(pyrimidin-

-yl)-1 H-ind ol-1 yl)acetyl)-M-(6bromopyridin-2-yl)-2azabicyclo[3.1.0]hex an-3 -carboxamide l-(2-((2S,4R)- 2-(3- *** 1.75(A) 555 chloro-2fluorobenzylcarbamoyl)-4-fluoropyrrolidin1 -yl)-2-oxoethyl)-5 (pyrimidin-5-yl)-1Hpyrazolo[3,4c]pyridine-3 carboxamide l-(2-((2S,4R)-2-(2'- *** 2.47(A) 617 chloro-2-fluorobiphenyl-

-ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(pyrimide in-5-yl)-1Hpyrazolo[3,4-

c]pyridine-3 carboxamide

- 74 043505

(2S,4R)-l-(2-(3- *** 2.58 (A) 614 acetyl-5 -(pyride azin4-yl)-1 H-ind ol-1 yl)acetyl)-M-(2' chloro-2-fluorobiphenylZyl)-4fluoropyrrolidine-2carboxamide (2S,4R)-l-(2-(3- *** 2.05 (A) 595 acetyl-5-(2methoxypyrimidin-5yl)-1 H-ind ol-1 yl )acetyl)-M-(6bromopyridin-2-yl)-4fluoropyrrolidin-2carboxamide ll-(2-((2S,4R)-2-(6- *** 1.19(A) 586 bromopyridin-2ylcarbamoyl)-4fluoropyrrolidine-1 yl)-2-oxoethyl)-5 -(1 methyl-1,2,3,6tetrahydropyridin-4yl)-1 H-ind azol-3 carboxamide

- 75 043505

(2S,4R)-l-(2-(3- *** 2.24(A) 520 acetyl-5 -(pyride azin4-yl)-1 H-ind ol-1 yl)acetyl)-M-(6chloropyridin- 2-yl)-4fluoropyrrolidine-2carboxamide l-(2-((2S,4R)-2-(6- *** 2.23 (A) 522 chloropyridin-2ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5 (azin-4-yl pyride)-1Nindazol-3carboxamide l-(2-((2S,4R)-2-(6- *** 1.60(A) 567 bromopyridin-2ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2- oxoethyl)-5(azin-4-yl pyride)-1Nindazole-3carboxamide

- 76 043505

(2S,4R)-1-(2-(3- *** 2.42(A) 683 acetyl-5-(2(pyrrolidin-1yl)pyrimidin-5-yl)1H-indol-1yl)acetyl)-M- (2'chloro-2-fluorobiphenyl3-yl)-4fluoropyrrolidin-2carboxamide (2S,4R)-1-(2-(3- *** 2.16(A) 644 acetyl-5-(2methoxypyrimidin-5yl)-1H-indole -1yl)acetyl)-H-(2'chloro-2-fluoro-[1,Hbiphenyl]-3-yl)-4fluoropyrrolidin-2carboxamide (2S,4R)-1-(2-(3- *** 2.07( A) 659 acetyl-5 -(1 -acetyl1,2,3,6tetrahydropyridin-4yl)-1 H-ind ol-1 yl)acetyl)-M-(2'chloro-2-fluorobiphenyl3-yl)-4fluoropyrrolidine-2carboxamide

- 77 043505

l-(2-((2S,4R)-2-(2'- *** 2.01 (A) 646 chloro-2-fluorobiphenyl3 -ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5-(2methoxypyrimidine -5yl)-1 H-ind azol-3 carboxamide l-(2-((2S,4R)-2-(6- *** 1.43 (A) 553 chloropyridin-2ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2- oxoethyl)-5-(2methoxypyrimidin-5yl)-1 H-ind azol-3 carboxamide (2S,4R)-l-(2-(3- *** 2.21 (A) 698 acetyl-5-(4(pyrimidin- 2yl)piperazin-1 -yl)1 N-indol-1yl)acetyl)-M-(2'chloro-2-fluorobiphenyl3-yl)-4fluoropyrrolidin-2carboxamide

- 78 043505

(2S,4R)-l-(2-(3acetyl-5-(4-(5fluoropyrimidin-2yl)piperazin-1 -yl)1H-indol-1yl)acetyl)-M-(2'chloro-2-fluorobiphenyl3- yl)-4fluoropyrrolidin-2carboxamide (2S,4R)-l-(2-(3acetyl-5-(4(methylsulfonyl)piperazin-1-yl)-1Nindol-1-yl)acetyl)-M(2- chloro-2fluorobiphenyl-3 -yl)-4fluoropyrrolidin-2carboxamide (2S,4R)-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-X- (2(benzo[c!]thiazol2yl)phenyl)-4fluoropyrrolidine-2carboxamide

2.43(A)

2.09(A)

3.91(V)

716

698

619

- 79 043505

(2S,4R)-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-X(benzo[<1]thiazol-2-ylmethyl)- 4fluoropyrrolidine-2carboxamide (2S,4R)-l-(2-(3acetyl-5 -(pyride azin4-yl)-1 H-ind ol-1 yl)acetyl)-M-(4,7difluoro-2,3-dihydro1 H-ind en-1 -yl)-4fluoropyrrolidin-2carboxamide (2S,4R)-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-4- fluoro-M(pyr idin-3 yl)pyrrolidine-2carboxamide

2.33 (V) 557

2.89 (V) 562

2.08 (V) 487

- 80 043505

(2S,4R)-l-(2-(3- *** 2.03 (B) 501 acetyl-5 -(pyride azin4-yl)-1 H-ind ol-1 yl)acetyl)-4-fluoro-I (pyridin-2-ylmethyl)pyrrolidin-2carboxamide l-(2-((2S,4R)-4^Top-** 2.77(B) 503

2-(pyridin-3ylmethylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-4-yl pyride)-1Nindazol-3carboxamide (2S,4R)-l-(2-(3-** 0.58(B ) 501 acetyl-5 -(pyridin4-yl)-1 H-ind ol-1 yl)acetyl)-4-fluoro-M(pyridin-4-ylmethyl)pyrrolidin-2carboxamide

- 81 043505

l-(2-((2S,4R)-2-(2- * 3.49(B) 621 (benzo[<1]thiazol-2yl)phenylcarbamoyl)4-fluoropyrrolidin-1 yl)-2-oxoethyl)-5( pyri dazi n-4-i l)-1Nindazol-3carboxamide (2S,4R)-l-(2-(3- * 3.24(B) 595 acetyl-5 -(azin4-yl pyride)-1 H-ind ol- 1 yl)acetyl)-4-fluoro-M(6(trifluoromethyl)benzo[0]isoxazol-3yl)pyrrolidine-2carboxamide l-(2-((2S,4R)-2-(4,7-** 2.69( B) 564 difluoro-2,3-dihydro-

N-indium-1ylcarbamoyl)-4fluoropyrrolidin-1yl)-2-oxoethyl)-5(pyride azin-4-yl)-1Nindazol-3carboxamide

- 82 043505

(2S,4R)-l-(2-(3- *** 2.78(B) 534 acetyl-5 -(pyride azin4-yl)-1 H-ind ol-1 yl)acetyl)-M-(3 chlorobenzyl )-4fluoropyrrolidine-2carboxamide l-(2-((2S,4R)-2-(3- *** 2.48 (B) 536 chlorobenzylcarbamoyl )-4-fluoropyrrolidin1 -yl)-2-oxoethyl)-5 (azin-pyride 4-yl)-1Nindazol-3carboxamide (2S,4R)-l-(2-(3- *** 2.98 (B) 552 acetyl-5 -(pyride azin4-yl)-1 H-ind ol-1 yl) acetyl)-N-(3-chloro5-fluorobenzyl)-4fluoropyrrolidine-2carboxamide

1-(2-((28.4V)-4-fluoro- * 3.34(B) 489

2-(pyridin-3ylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(pyridin-4-yl)-1Nindazol-3carboxamide

- 83 043505

1-(2-((28,4R)-2-(2ethyl-3OXOISOINDOLIN-5ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(azin-4-yl pyride)-1Nindazol-3carboxamide (2S,4R )-l-(2-(3acetyl-5 -(pyr id azin4-yl)-1 H-ind ol-1 yl)acetyl)-M-(2-ethyl3-oxoisoind olin-5 yl)-4fluoropyrrolidin-2carboxamide

-(2-((28.4R)-2(benzo[O]thiazol-6ylcarbamoyl)-4fluoropyrrolidin-1yl)-2-oxoethyl)-5(pyridazin-4-yl)-1Nindazol-3carboxamide

1.97(B) 571

2.49 (V) 569

2.03 (V) 545

- 84 043505

l-(2-((2S,4R)-2- * 2.81 (B) 586 ((lR,2S)-2(benzyloxy)cyclopentylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(azine pyride -4-yl)-1Nindazol-3carboxamide l-(2-((2S,4R)-2- * 2.15(B) 559 (benzo[P]thiazol-2ylmethylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)- 5(azin-4-yl pyride)-1Nindazol-3carboxamide (2S,4R)-l-(2-(3-** 2.91 (B) 553 acetyl-5 -(azin4-yl pyride)-1 N-indol -1 yl)acetyl)-M-(2,3dimethyl-1 H-indol5 yl)-4fluoropyrrolidine-2carboxamide

- 85 043505

(2S,4R)-l-(2-(3- * 4.15(B) 623 acetyl-5 -(pyride azin4-yl)-1 H-ind ol-1 yl)acetyl)-4-fluoro-K(4 -(5,6,7,8tetrahydronaphthalene2-yl)thiazol-2yl)pyrrolidine-2carboxamide

1-(2-((28.4K)-4-fluoro- * 3.88(B) 625

2-(4-(5,6,7,8tetrahydronaphthalene2-yl)thiazol-2ylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-4-yl pyride)-1Nindazol-3carboxamide (2S,4R)- l-(2-(3- ** 2.41 (B) 543 acetyl-5 -(pyride azin4-yl)-1 H-ind ol-1 yl)acetyl)-M(benzo[<1]thiazol-6-yl )4-fluoropyrrolidine-2carboxamide

- 86 043505

(2S,4R)-l-(2-(3acetyl-5 -(pyride azin4-yl)-1 H-indol-1 yl)acetyl)-4-fluoro-H(4-(6methylimidazo[2,1 b] pyridin-5yl)pyridin-2yl)pyrrolidin-2carboxamide l-(2-((2S,4R)-4-φτop2-(4-(6methylimidazo[2,1 b]pyridin-5yl)thiazol-2ylcarbamoyl)pyrrolidine-1 -yl)-2oxoethyl)-5(pyrid azin-4-yl)-1Nindazole-3carboxamide (2S,4R)-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-indol-1 yl)acetyl)-4-fluoro-H(pyridin-3-ylmethyl)pyrrolidin-2carboxamide (2S,4R)-l-(2-(3acetyl-5 -(pyride azin4-yl)-1 H-indol-1 yl)acetyl)-H-(6(benzyloxy)pyridin2-yl)-4fluoropyrrolidine-2carboxamide

2.25 (V)

1.83 (V)

0.62 (V)

3.63(V)

629

631

501

593

- 87 043505

(9H-fluoren-9yl)methyl(4-((28.4K)-1 (2-(3-acetyl-5(azin-4-yl pyride)-1Nindol-1-yl)acetyl)-4fluoropyrrolidine-2carboxamido) benzyl) carbamate

3.81 (V) 737

l-(2-((2S,4R)-2-(3- *** 2.61 (B) 554 chloro-5fluorobenzylcarbamoyl)-4-fluoropyrrolidin1 -yl)-2-oxoethyl)-5 (azin-4-yl pyride )-1Nindazole-3carboxamide

- 88 043505

l-(2-((2S,4R)-2-(2,3-** 2.55 (B) 555 dimethyl-1 H-ind ol-5 ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5 (azin-4yl pyride)-1Nindazol-3carboxamide (2S,4R)-l-(2-(3- * acetyl-5 -(azin4-yl pyride)-1 H-ind ol-1 yl)acetyl)-4- fluoro-M(2-(2oxooxazolid in-3 yl)phenyl)pyrrolidine -2-carboxamide l-(2-((2S,4R)-4-φτop- *

2-(2-(2oxooxazolid in-3yl)phenylcarbamoyl)p irrolidin-1-yl)-2oxoethyl)-5(azin-4yl pyride)-1Nindazol-3carboxamide

2.29 (V) 571

1.63 (V) 573

- 89 043505

(2S,4R)-l-(2-(3- *** 2.63 (B) 521 acetyl-5 -(pyride azin4-yl)-1 H-ind ol-1 yl)acetyl)-M-(5chloropyr idine -3 -yl)-4fluoropyrrolidine-2carboxamide l-(2-((2S,4R)-2-(5- ** 2.34(B) 523 chloropyridin-3 ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)- 5(azin-4-yl pyride)-1Nindazol-3carboxamide (2S,4R)-l-(2-(3- *** 2.79(B) 565 acetyl-5 -(azin4-yl pyride)-1 H-ind ol-1 yl)acetyl)-M-(5bromopyrrolidine-3-yl)-4fluoropyrrolidine-2carboxamide l-(2-((2S,4R)-2-(5-(3,4- * 3.61 (B) 640 dichlorophenyl)-1,3,4thiadiazol-2ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(azin-4-yl pyride)-1Nindazol-3carboxamide

- 90 043505

l-(2-((2S,4R)-2-(4(aminomethyl)phenyl rbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(azin-4-yl pyride)-1Nindazol-3carboxamide l-( 2-((2S,4R)-4-φτop2-(2-(5-methyl-1Hpyrazol-1yl)phenylcarbamoyl)p irrolidin-1-yl)-2oxoethyl)-5(azin-4-yl pyride)-1Nindazol- 3carboxamide (2S,4R)-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-indol-1 yl)acetyl)-4-fluoro-M(2-(5-methyl- 1Hpyrazol-1yl)phenyl)pyrrolidine-2-carboxamide

0.42(B) 517

2.54 (V) 568

2.84 (V) 566

- 91 043505

l-(2-((2S,4R)-2-(6- * 3.43 (B) 595 (benzyloxy)pyridin2-ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(azin-4-yl pyride )-1Nindazole-3carboxamide (2S,4R)-l-(2-(3- * 3.53 (B) 598 acetyl-5 -(pyride azin4-yl)-1 H-ind ol-1 yl)acetyl)-M- ((1 S,2S)2(benzyloxy)cyclohexyl)-4fluoropyrrolidine-2carboxamide (2S,4R)-l-(2-(3- *** 3.14(B) 556 acetyl-5 -(azin4-yl pyride) -1 H-ind ol-1 yl)acetyl)-M-(2,2dimethyl-2,3benzofuran-6-yl)-4fluoropyrrolidin-2carboxamide

- 92 043505

l-(2-((2S,4R)-2-(2,2- *** 2.92(B) 558 dimethyl-2,3 dihydrobenzofuran-6ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5( pyride azin-4-yl)-1Nindazol-3carboxamide (2S,4R)-l-(2-(3- * 3.33 (B) 584 acetyl-5 -(pyride azin4-yl)-1 H-ind ol-1 yl )acetyl)-M-((1 S,2S)2(benzyloxy)cyclopentyl)-4fluoropyrrolidine-2carboxamide l-(2-((2S,4R)-2- * 3.38(B) 600 ((lS,2S) -2(benzyloxy)cyclohexilcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(azin-4-yl pyride)-1Nindazole-3carboxamide

- 93 043505

l-(2-((2S,4R)-4^Top- * 2.10(B) 426

2(methylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-4-yl pyride)-1Nindazol-3carboxamide (lR,3S,5R)-2-(2-(3-*** 2.36(A ) 638 acetyl-5-(2methoxypyrimidin-5yl)-1 H-ind ol-1 yl)acetyl)-M-(2'chloro-2-fluorobiphenyl3-yl)-2azabicyclo[3.1.0]hex an-3-carboxamide (lR,3S,5R)-2-(2-(3- *** 1.91 (A) 591 acetyl-5-(2methoxypyrimidin-5yl)-1 H-ind ol-1 yl)acetyl)-M-(6bromopyridine -2-yl)-2azabicyclo[3.1.0]hex an-3-carboxamide

- 94 043505

(2S,4R)-l-(2-(3- *** 1.97(A) 592 acetyl-5-(2cyanopyrimidin-5yl)-1 H-indol-1 yl)acetyl)-M-(6bromopyridin-2- yl)-4fluoropyrrolidine-2carboxamide (2S,4R)-l-(2-(3- *** 1.86(A) 585 acetyl-5-(2fluoropyrimidin-5yl)-1 H-indol-1 yl)acetyl)-M -(6bromopyridin-2-yl)-4fluoropyrrolidin-2carboxamide (2S,4R)-l-(2-(3- *** 1.58(A) 581 acetyl-5-(2methylpyrimidin-5yl)-1 H-indol-1 yl)acetyl)-M-(6bromopyridin-2-yl)-4fluoropyrrolidin-2carboxamide (2S,4R)-l-(2-(3- * 0.69(B) 515 acetyl-5 -(azin4-yl pyride)-1 N-indol-1 yl)acetyl)-M-(4(aminomethyl)phenyl)4-fluoropyrrolidine-2carboxamide

- 95 043505

l-(2-((2S,4R)-2-(lH- * 2.04(B) 528 indazol-6ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(azin-4-yl pyride)-1Nindazole -3carboxamide (2S,4R)-l-(2-(3- ** 1.83 (B) 424 acetyl-5 -(azin4-yl pyride)-1 H-ind ol-1 yl)acetyl)-4-fluoro- Mmethylpyrrolidine-2carboxamide (2S,4R)-l-(2-(3- *** 2.56(B) 522 acetyl-5 -(pyride azin4-yl)-1 H-ind ol-1 yl)acetyl)-H- (6chloropyrazin-2-yl)-4fluoropyrrolidin-2carboxamide l-(2-((2S,4R)-2-(6- *** 2.43 (B) 524 chloropyrazin-2ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl )-5(azin-4-yl pyride)-1Nindazole-3carboxamide

- 96 043505

l-(2-((2S,4R)-2-(5- ** 2.40(B) 567 bromopyridin-3 ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(azin-4-yl pyride) -1Nindazole-3carboxamide l-(2-((2S,4R)-4^Top- * 2.59(B) 641

2-(4-fluoro-3-(6,7,8,9tetrahydro5H[1,2,4]triazolo[4,3-

a] azepin-3 - yl)phenylcarbamoyl) p irrolidin-1 -yl)-2oxoethyl)-5(azin-4-yl pyride)-1Nindazol-3carboxamide (2S,4R)-l-(2-(3- 2.78 ( B) 639 acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-4-fluoro-X(4-fluoro-3-(6,7,8,9tetrahydro5H[1,2 ,4]triazolo[4,3-

a] azepin-3 - yl)phenyl)pyrrolidine -2-carboxamide

- 97 043505

l-(2-((2S,4R)-2-(3-*chloro-2(trifluoromethyl)phenylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(azin-4-yl pyride)-1Nindazole -3carboxamide l-(2-((2S,4R)-2-(3-(2,4- * d ichlor orphenyl)-1Hpyrazol-4ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(pyrid azin-4-yl)-1Nindazol-3carboxamide (2S,4R)-l-(2-(3- * acetyl-5 -(azin4-yl pyride)-1 H-indol-1yl)acetyl)-N- (3-chloro2-(1Η-1,2,4-triazol-1yl)phenyl)-4fluoropyrrolidine-2carboxamide

3.24(B) 590

2.62 (V) 622

2.31(B) 587

- 98 043505

l-(2-((2S,4R)-2-(3- * chloro-2-(1H-1,2,4triazol-1yl)phenylcarbamoyl)4-fluoropyrrolidin-1 yl)-2-oxoethyl)-5( pyride azin-4-yl)-1Hindazol-3carboxamide (2S,4R)-l-(2-(3- * acetyl-5 -(pyride azin4-yl)-1 H-indol-1 yl)acetyl)-4 -fluoro-M(5-methyl-2(trifluoromethyl)[1,2,4]triazol[1,5a]pyrimidin-7yl)pyrrolidine-2carboxamide

1-(2-((28.4K)-4-fluoro-*

2-(2-(4-methyl-4H1,2,4-triazol-Zyl)phenylcarbamoyl)p-irrolidin-1-yl)-2oxoethyl)-5(azin-4-yl pyride)-1Hindazol-3carboxamide

1.94(B) 589

2.46 (V) 610

2.42 (V) 569

- 99 043505

(2S,4R)-l-(2-(3- *** 3.29(B) 604 acetyl-5 -(pyride azin4-yl)-1 H-ind ol-1 yl)acetyl)-M-(3 - (2chlorophenyl)-1,2,4thiadiazol-5-yl)-4fluoropyrrolidine-2carboxamide (2S,4R)-l-(2-(3- *** 2.45 (A) 599 acetyl-5-(2chlorophenyl)-1Nindol- 1 -yl)acetyl)-M(6-bromopyridin-2yl)-4fluoropyrrolidin-2carboxamide l-(2-((2S,4R)-2-(6- *** 1.40(A) 583 bromopyridin-2ylcarbamoyl)-4fluoropyrrolidine -1 yl)-2-oxoethyl)-5-(2methylpyrimidin-5yl)-1 H-ind azol-3 carboxamide

- 100 043505

(2S,4R)-l-(2-(3- * acetyl-5-(2methylpyrimidin-5yl)-1 H-ind ol-1 yl)acetyl)-M-(2'chloro-2-fluorobiphenyl3-yl) -4fluoropyrrolidin-2carboxamide l-(2-((2S,4R)-2-(2'-*chloro-2-fluorobiphenyl3 -ylcarbamoyl)-4fluoropyrrolidin-1yl)-2-oxoethyl)-5-(2methylpyrimidin-5yl) -1 H-ind azol-3 carboxamide l-(2-((2S,4R)-4-φτop- *

2-(2-(pyridin-2yl)isoindolin-4ylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-4-ylpyride)-1Nindazol-3carboxamide

2.10(A) 628

1.91 (A) 630

1.91 (V) 606

- 101 043505

105

(2S,4R)-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-indol-1 yl)acetyl)-4-fluoro-H(2-(pyridin2yl)isoindolin-4yl)pyrrolidine -2carboxamide

1.97(B) 604

106 (2S,4R)-l-(2-(32.94 (V) 641

acetyl-5 -(pyride azin4-yl)-1 H-indol-1 yl)acetyl)-4-fluoro-H(2-(4fluoroenyl)4,5,6,7tetrahydrobenzo[(1]thiazol-7yl)pyrrolidine -2carboxamide

- 102 043505

107

108

109

1-(2-((28,4R)-4-φτop2-(2-(4-fluorophenyl)4,5,6,7-tetrahydrobenzo[c!]thiazol-7ylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl )-5(azin-4-yl pyride)-1Nindazole-32.97 (B)

643 carboxamide (2S,4R)-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-M-(5bromopyrimidin-2yl)-4fluoropyrrolidine-2carboxamide

-(2-((28.4R)-2-(5bromopyrimidin-2ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(azin-4-yl pyride)-1Nindazol-31.85 (B)

1.86(B)

566

568 carboxamide

- 103 043505

(2S,4R)-l-(2-(3- * 3.14(B) 536 acetyl-5 -(pyride azin4-yl)-1 H-ind ol-1 yl)acetyl)-4-fluoro-H(naphthalene -2yl)pyrrolidin-2carboxamide (2S,4R)-l-(2-(3- ** 1.75(B) 508 acetyl-5 -(pyridine azin4-yl)-1 H-ind ol-1 yl)acetyl)- 4-fluoro-H((lS,2S)-2hydroxycyclohexyl)pyrrolidine-2carboxamide

1-(2-((28.4V)-4-fluoro- * 2.95 (V) 597

2-(6(trifluoromethyl)benzo[<1]isoxazol-3ylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-4-yl pyride)-1Nindazol-3 carboxamide

- 104 043505

FROM

114

115

l-(2-((2S,4R)-4^ _T op- *

2-(5-methyl-2(trifluoromethyl)[1,2,4]triazol[1,5a]pyrimidin-7ylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-4-ylpyride)-1Nindazole -3carboxamide l-(2-((2S,4R)-2-(3-(2-**chlorophenyl)-1,2,4thiadiazol-5ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(pyride azin-4-yl)-1Nindazol-3carboxamide l-(2-((2S,4R)-2-(5-(2-*chlorophenyl)-1,3,4thiadiazol-2ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2 -oxoethyl)-5(azin-4-yl pyride)-1Nindazole-32.07 (B) 612

2.89 (V) 606

2.67 (B) 606 carboxamide

- 105 043505

116

F

(2S,4R)-l-(2-(3- ** 3.30(B) 604 acetyl-5 -(pyride azin4-yl)-1 H-ind ol-1 yl)acetyl)-M-(5-( 2chlorophenyl)-1,3,4thiadiazol-2-yl)-4fluoropyrrolidine-2carboxamide

117 (2S,4R)-l-(2-(33.73 (V) 638

acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-M-(5-(3,4dichlorophenyl)-1,3,4thiadiazol-2-yl)-4fluoropyrrolidin-2carboxamide

(2S,4R)-l-(2-(5-(2- *** 1.44(A) 622 acetamidopyrimidine-

-yl)-3-acetyl-1H- indol-1 -yl)acetyl)-M(6-bromopyridin-2yl)-4fluoropyrrolidin-2carboxamide

- 106 043505

(2S,4R)-l-(2-(3- *** 2.54(A) 599 acetyl-5-(3chlorophenyl)-1Nindol-1-yl)acetyl)-M(6-bromopyridin-2yl)-4fluoropyrrolidin- 2carboxamide (2S,4R)-l-(2-(3- *** 1.34(A) 578 acetyl-5-(6methylpyridin-3-yl)-

H-ind ol-1 yl)acetyl)-M-(6bromopyridin-2-yl)-4fluoropyrrolidine-2carboxamide (2S,4R)-l-(2-(3- *** 1.96(A) 628 acetyl-5- (6methylpyridazin-4yl)-1 H-ind ol-1 yl)acetyl)-H-(2'chloro-2-fluorobiphenyl3-yl)-4fluoropyrrolidin-2carboxamide

- 107 043505

122

123

124

( 2S,4R)-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-4-fluoro-M(8-methoxy-6methylchroman-4yl)pyrrolidin- 2carboxamide

1-(2-((28,4R)-4-φτop2-(l-(2-φτop-5methylphenyl)-2oxopiperidin-3 ylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-4-pyride yl)-1Nindazole-3carboxamide**

2.38 (V) 588

2.58/2.7 586

3(B)

2.61 (V) 617

- 108 043505

(2S,4R)-l-(2-(3- ** 2.92(B) 615 acetyl-5 -(pyride azin4-yl)-1 H-ind ol-1 yl)acetyl)-4-fluoro-H( 1-(2-fluoro-5methylphenyl)-2oxopiperidin-3 yl)pyrrolidine-2carboxamide (2S,4R)-l-(2-(3- * 3.09(B) 588 acetyl-5 -(azin4-yl pyride)-1 H-ind ol-1 yl)acetyl)-M-(3-chloro2(trifluoromethyl)phenyl)-4-fluoropyrrolidine2-carboxamide (2S,4R)-l-(2-(3- *** 2.47(B) 566 acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-M-(6bromopyrazin-2-yl)-4fluoropyrrolidin-2carboxamide

- 109 043505

l-(2-((2S,4R)-2-(6- *** 2.22(B) 568 bromopyrazin-2ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(azin-4-yl pyride) -1Nindazole-3carboxamide (2S,4R)-l-(2-(3- ** 3.19(B) 584 acetyl-5 -(azin4-yl pyride)-1 H-ind ol-1 yl)acetyl)-4- fluoro-M(2,2,6trifluorobenzo[s!][1,3]d ioxol-5yl)pyrrolidine-2carboxamide l-(2-((2S,4R)-4-φτop-** 2.86(B) 586

2-(2,2,6trifluorobenzo[s!][1,3]d ioxol-5ylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-4-yl pyride)-1Nindazol-3carboxamide

- 110 043505

1-(2-((28.4R)-4-fluoro-* 2.77(B) 538

2-(naphthalene-2ylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-4-yl pyride)-1Nindazol-3carboxamide (lR,3S,5R)-2-(2-(3- *** 1.74(A) 573 acetyl-5-(2methylpyrimidin-5yl)-1 H-ind ol-1 yl)acetyl)-M-(6bromopyridin-2-yl)-2azabicyclo[3.1.0]hex an-3-carboxamide ( lR,3S,5R)-2-(2-(3- *** 2.21 (A) 622 acetyl-5-(2methylpyrimidin-5yl)-1 H-ind ol-1 yl)acetyl)-M-(2' chloro-2-fluorobiphenyl3-yl)-2azabicyclo[3.1.0]hex an-3-carboxamide

- 111 043505

(lR,3S,5R)-2-(2-(3- *** 1.71 (A) 560 acetyl-5-(2methylpyrimidin-5yl)-1 H-ind ol-1 yl)acetyl)-M-(3 -chloro2-fluorobenzyl)-2azabicyclo[3.1.0]hex an-3 -carboxamide (2S,4R)-l-(2-(3- *** 1.64(A) 566 acetyl-5-(2methylpyrimidin-5yl)- 1 H-ind ol-1 yl)acetyl)-M-(3-chloro2-fluorobenzyl)-4fluoropyrrolidine-2carboxamide (2S,4R)-l-(2-(3- *** 1.80(A) 582 acetyl-5 -(2methoxypyrimidin-5yl)-1 H-ind ol-1 yl)acetyl)-M-(3-chloro2-fluorobenzyl)-4fluoropyrrolidine-2carboxamide

- 112 043505

(2S,4R)-l-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indol-1yl)acetyl)-M-(6chloropyridin-2-yl)-4fluoropyrrolidin-2carboxamide (2S,4R) -l-(2-(5-(2acetamidopyrimidin5 -yl)-3 -acetyl-1Nindol-1 -yl)acetyl)-M(2 '-chloro-2 fluorobiphenyl-3 -yl)-4fluoropyrrolidin-2carboxamide *** * **

1.53(A)

1.95(A)

535

671

1-(2-((2S,4R)-44top-** 3.38(B) 503

2-(pyridin-2ylmethylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-4-ylpyride)-1Nindazol-3carboxamide

- 113 043505

141

140

142

(2S,4R)-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-4-fluoro-H(1-(1 -methyl- 1Hpyrazole -4yl)piperide in-3 yl)pyrrolidine-2carboxamide

-(2-((2 S,4R)-4-φτop2-(1-(1 -methyl-1Hpyrazol-4yl)piperide in-3 ylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-pyride 4-yl)-1Nindazol-3carboxamide (2S,4R)-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1H-indol-1yl)acetyl)-4-fluoro-H( 1H-indazol-6yl)pyrrolide in-2** **

1.51 (V) 573

2.37 (V) 575

2.10(B) 526 carboxamide

- 114 043505

(2S,4R)-l-(2-(3- * 1.59(B) 494 acetyl-5 -(pyride azin4-yl)-1 H-ind ol-1 yl)acetyl)-4-fluoro-M(( lR,2R)-2hydroxycyclopentyl)pyrrolidin-2carboxamide (2S,4R)-l-(2-(3- * 1.43 (B) 503 acetyl-5 -(pyride azin4-yl)-1 H-ind ol-1 yl) acetyl)-4-fluoro-M(6-hydroxypyridin2-yl)pyrrolidine-2carboxamide

1-(2-((28.4K)-4-fluoro- * 1.66(B) 496

2-((lR,2R)-2hydroxycyclopentyl carbamoyl)pyrrolidi and-1-yl)-2-oxoethyl)-5 (azin-4-yl pyride)-1Nindazol-3carboxamide

- 115 043505

l-(2-((2S,4R)-2-(3-(3- * 3.47(B) 606 chlorophenyl)-1,2,4thiadiazol-5ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5 (azin-4-yl pyride)-1Nindazol-3carboxamide (2S,4R)-l-(2-(3- * 3.67(B) 604 acetyl-5 -(azin4-yl pyride)-1 H-ind ol-1 yl)acetyl)-I-(3 -(3 chlorophenyl)-1,2,4thiadiazol-5-yl)-4fluoropyrrolidine-2carboxamide (2S,4R)-l-(2-(3- *** 1.49(A) 580 acetyl-5-(6methylpyridin-3 yl)-1 H-ind ol-1 yl)acetyl)-M-(6bromopyridin-2-yl)-4fluoropyrrolidin-2carboxamide

- 116 043505

(2S,4R)-l-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-ind ol-1 yl)acetyl)-X-(2,2'dichlorobiphenyl-3 yl)4-fluoropyrrolidin- 2carboxamide (2S,4R)-l-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-ind ol-1 yl)acetyl)-M-(2'chloro-2,4',5'trifluorobiphenyl -3 yl)-4fluoropyrrolidin-2carboxamide (2S,4R)-l-(2-(3acetyl-5-(6methylpyridin-3 -yl)1 H-ind ol-1 yl)acetyl)-M-(2'chloro -2-fluorobiphenyl3-yl)-4fluoropyrrolidine-2carboxamide *** 2.17(A) 644 *** 2.22 (A) 664 *** 1.91 (A) 627

- 117 043505

1-(2-((28.4Κ)-4-φτορ- *

2-(2-methyl-3-oxo-3,4dihydro-2Hbenzo[b] [1,4]oxazin5ylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(pyride azin-4-yl)-1Nindazol-3carboxamide (2S,4R)-l-(2-(3- * acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-4-fluoro-M(2-methyl-3 - oxo-3,4dihydro-2Hbenzo[b][1,4]oxazin5 -yl)pyrrolidine-2carboxamide

-(2-((28.4R)-4-φτop- *

2-(4hydroxypyridin-2ylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-4-ylpyride)-1Nindazol-3carboxamide

1.97(B) 573

2.31(B) 571

2.17(B) 505

- 118 043505

155

156

157

1-(2-((28.4Κ)-4-φτορ- *

2-(1-(1 -methyl-1Hpyrazol-3-yl)-2oxopyrrolidin-3ylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-4-yl pyride)-1Nindazol-3carboxamide (2S,4R )-l-(2-(3- * acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-M-(3 -(2,4dichlorophenyl)- 1Hpyrazol-4-yl )-4fluoropyrrolidine-2carboxamide

1-(2-((28.4R)-4-fluoro-*

2-(pyridin-4ylmethylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-4-ylpyride)-1Nindazol-3carboxamide

1.19(B) 575

2.98 (V) 620

0.37 (V) 503

- 119 043505

158

159

160

l-(2-((2S,4R)-4-φτop2-( 1 -(2-fluorophenyl)-3 methyl-1 H-pyrazol-5 ylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(pyride azin-4-yl)-1Nindazol-3carboxamide l-(2-((2S,4R)-2-(l-(2chlorophenyl)-2oxopiperidin-3 ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5( pyrid azin-4-yl)-1Nindazol-3carboxamide (2S,4R)-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-indol-1 yl)acetyl)-4-fluoro- M(1 -(2-fluorophenyl)-3 methyl-1 H-pyrazol-5 yl)pyrrolidine-2carboxamide

2.49 (V) 586

2.46 (V) 619

2.36 (V) 584

- 120 043505

(2R,4S)-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-M-( 1 -(2chlorophenyl)-2oxopiperid in-3 - yl)4-fluoropyrrolidin-2carboxamide (2S,4R)-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-4-fluoro-H(1 -(5-fluoro-3methylbenzofuran-2yl)ethyl)pyrrolidine2-carboxamide *** 2.85 (B) 617 ** 3.52(B) 586 (2S,4R)-l-(2-(3acetyl-5-(2methylpyrimidin-5yl )-1 H-ind azol-1 yl)acetyl)-H-(2'chloro-2-fluorobiphenyl3-yl)-4fluoropyrrolidine-2carboxamide *** 2.23 (A) 629

- 121 043505

(2S,4R)-l-(2-(3- *** 1.65(A) 629 acetyl-5-(2methylpyrimidin-5yl)-1 H-ind ol-1yl)acetyl)-I-(3 -(3 chlorpyridin-2yl)-2fluorophenyl)-4fluoropyrrolidine-2carboxamide (2S,4R)-l-(2-(3- *** 1.75(A) 580 acetyl-5-(2methylpyrimidin-5yl)-1 H-ind azol-1 yl)acetyl)-M-(6bromopyridin-2-yl)-4fluoropyrrolidin-2carboxamide (2S,4R)-l-(2-(3- 2.26 (B) 521 acetyl-5 -(azin4-yl pyride)-1 H -ind ol-1 yl)acetyl)-M-(2chloropyr idin-3 -yl)-4fluoropyrrolidin-2carboxamide

- 122 043505

167

(2S,4R)-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-4-fluoro-X(1-(1 -methyl- 1Hpyrazole -3 -yl)-2oxopyrrolidine-3 2.15(B) 573 yl)pyrrolidine-2carboxamide

168

169

2.20 (B) 576 l-(2-((2S,4R)-2-(2cyclohexyl-5-oxo2,5-dihydro-1Hpyrazol-3ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(azine pyride -4-yl)-1Nindazol-3carboxamide (2S,4R)-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-4-fluoro-M (5-methyl-4-phenyl-1Hpyrazol-3yl)pyrrolidine-22.88 (B) 566 carboxamide

- 123 043505

170

1-(2-((28.4Κ)-4-φτορ2.58 (V) 568

171

Ό

2-(5-methyl-4-phenyl1H-pyrazol-3ylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-4-yl pyride)-1Nindazol-3carboxamide (2S,4R)-l-(2- (3acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-b1-(1,5__ dimethyl-6-oxo4,5,6,7-tetrahydro-1Hpyrazolo[3.41.26 (B)573

172

b]pyridin-3-yl)-4fluoropyrrolidin-2carboxamide

-(2-((28,4R)-4-φτop2-((1 S,2S)-2hydroxycyclohexyl carbamoyl)pyrrolidin n-1 -yl)-2-oxoethyl)-5 (azin-4-yl pyride)-1Nindazole -31.54(B) 510 carboxamide

- 124 043505

173

174

175

(2S,4R)-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-4-fluoro-M(3 -methyl-2-oxo-2 ,3 dihydropyrimidin-4yl)pyrrolidine-2carboxamide

1-(2-((28,4R)-4-φτop2-(6hydroxypyridin-2ylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-4-yl pyride)-1Nindazol-3carboxamide (2S,4R) -l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-4-fluoro-M(5 -hydroxypyridine in2-yl)pyrrolidine-2carboxamide

2.17(B) 518

1.71 (V) 505

2.25 (V) 503

- 125 043505

176

177

l-(2-((2S,4R)-4^ _T op2-(5hydroxypyridin-2ylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-4-yl pyride)-1Nindazol-3carboxamide (2S,4R )-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-4-fluoro-H(4-hydroxypyridin-2yl)pyrrolidine-2carboxamide

1.06(B) 505

2.08 (V) 503

178

l-(2-((2S,4R)-2-(4chloropyrimidin-2ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-53.26(B) 524 (azin-4-yl pyride)-1 Nindazol-3carboxamide

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179

180

181

182

l-(2-((2S,4R)-4-φτop2-(5-iodopyrimidin-2ylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-4-yl pyride)-1Nindazol-3carboxamide (2S, 4R)-l-(2-(3acetyl-5 -(pyr id azin4-yl)-1 H-ind ol-1 yl)acetyl)-H-(4chloropyrimidin-2-yl)4-fluoropyrrolidin-2carboxamide (2S, 4R)-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-4-fluoro-M(2-(4-methyl-4H-1, 2,4triazol-3yl)phenyl)pyrrolidine -2-carboxamide (2S,4R)-l-(2-(3acetyl-5 -(pyrid azin4-yl)-1 H-ind ol-1 yl)acetyl)-X -(5-(2chlorophenyl)-1,2,4oxad iazol-3 -yl)-4fluoropyrrolidin-2carboxamide

2.78(V)

3.57(V)

3.16 (V)

3.45(V)

616

522

567

588

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183

184

185

1-(2-((28.4R)-4^ _T op2-((R)-1 -(5-fluoro-3 methylbenzofuran-2yl)ethylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(pyride azin-4-yl)-1Nindazole-3carboxamide

-(2-((28.4R)-4-φτop2-((8)-1-(5-fluoro-3methylbenzofuran-2yl)ethylcarbamoyl)pyrrolidin-1-yl)-2oxoethyl)-5(azin-4 pyride -yl)-1Nindazole-3carboxamide

-(2-((28.4R)-2-(2chloropyridin-3 ylcarbamoyl)-4fluoropyrrolidin-1 yl)-2-oxoethyl)-5(azin-4-yl pyride)-1 Nindazol-33.02(B) 588

3.30(B) 588

1.70(B) 523 carboxamide

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(2S,4R)-l-(2-(3- *** 1.79(A) 630 acetyl-5-(2hydroxypyrimidin5 -yl)-1 H-ind ol-1 yl)acetyl)-M-(2'chloro -2-fluorobiphenyl3-yl)-4fluoropyrrolidin-2carboxamide (2S,4R)-l-(2-(3- *** 2.16(A) 687 acetyl-5-(2-(2methoxyethylamino)py rimidin-5 -yl) -1Nindol-1-yl)acetyl)-M(2'-chloro-2 fluorobiphenyl-3-yl)-4fluoropyrrolidin-2carboxamide (2S,4R)-l-(2-(3-*** 2.08 (A) 643 acetyl-5-(2(methylamino)pyrimid in-5 -yl)-1 H-ind ol-1 yl)acetyl)-M-(2'chloro-2-fluorobiphenyl3-yl)-4fluoropyrrolidine-2carboxamide

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2.37 (A) 623

(lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-ind azol-1 yl)acetyl)-M-(2'chloro-2-fluorobiphenyl3-yl)- 2azabicyclo[3.1.0]hex an-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-ind azol-1 yl)acetyl)-M- (6bromopyridin-2-yl)-2azabicyclo[3.1.0]hex an-3-carboxamide (2S,4R)-l-(2-(3acetyl-5-(2(trifluoromethyl)pyrim idin-5 -yl)-1 N-ind ol1 -yl)acetyl)-M-(2chloro-2-fluorobiphenyl3-yl)-4fluoropyrrolidine-2carboxamide

1.90(A) 574

2.64 (A) 682

Example 7: Analysis of human factor D.

Human factor D (purified from human serum, Complement Technology, Inc.) at a final concentration of 80 nM is incubated with test compound at various concentrations for 5 minutes at room temperature in 50 mM Tris, 1 M NaCl, pH 7.5. Synthetic substrate ZL-Lys-SBzl and DTNB (Ellman's reagent) are added to a final concentration of 100 µM each. Color enhancement is recorded at OD ₄₀₅ nm on a microplate in kinetic mode for 30 minutes with 30 second time points on a spectrofluorimeter. _IC50 values are calculated using nonlinear regression of the percentage inhibition of complement activity by factor D as a function of the concentration of the test compound.

Example 8 Hemolysis Assay.

The hemolysis assay was previously described by G. Ruiz-Gomez, et al., J. Med. Chem. (2009) 52:6042–6052. In the red blood cell (RBC) assay, rabbit red blood cells (purchased from Complement Technologies) are washed using GVB Buffer (0.1% gelatin, 5 mM Veronal, 145 mM NaCl, 0.025% NaN ₃ , pH 7.3) plus 10 mM final Mg-EGTA. Cells are used at a concentration of 1 x 10 ⁸ cells/ml. Prior to hemolysis analysis, the optimal concentration of Normal Human Serum (NHS) required to achieve 100% lysis of rabbit red blood cells is determined by titration. NHS (Complement Technologies) was incubated with the inhibitor for 15 min at 37°C, rabbit red blood cells in buffer were added and incubated for another 30 min at 37°C. Positive control (100% lysis) consists of serum and RBC and negative control (0% lysis) consists of Mg-EGTA buffer and RBC only. Samples were centrifuged at 2000 rpm for 5 min, and supernatants were collected. The absorbance of the supernatant was measured at 405 nm using a UV/visible spectrophotometer. The percentage of lysis in each sample is calculated relative to the positive control (100% lysis).

Example 9 Non-limiting Examples of Compounds of Formula I

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table 2

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This description has been disclosed with reference to embodiments of the invention. However, it will be apparent to one of ordinary skill in the art that various modifications and changes can be made without departing from the scope of the present invention as set forth in the claims below. Accordingly, the description is to be considered in an illustrative and not a restrictive sense, and all such modifications are intended to be included within the scope of the invention.

Including the text of priority documents

To provide full benefit to previously filed priority applications, the text of US Provisional Application 62/046783, filed September 5, 2014, is incorporated herein by reference and relevant portions are reproduced below. Where terms overlap, the term used in the claims shall be deemed to refer to the terms provided in Part A above unless otherwise stated or clear from the text of the claim, however, the entire disclosure is considered part of the invention for all purposes disclosed .

The present invention relates to compounds of formula I

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A (I) and their pharmaceutically acceptable salts. In formula I, variables, for example, A, B, L, X ¹ , X ² , Q ¹ , Q ² and Q ³ have the following meanings:

Q ¹ represents N(R1) or C(R1R1);

Q ² represents C(R ² R ² ), C(R ² R ² )-C(R ² R ² ) or C(R ² R ² )O;

Q ³ represents N(R ³ ), S or C(R ³ R ³ ');

(a) X ¹ and X ² are independently N or CH; or (b) X ¹ and X ² together represent C=C;

R ¹ , R ¹ , R ² , R ² , R ³ and R ³ are independently selected in each case from (c) and (d);

(c) hydrogen, halogen, hydroxyl, nitro, cyano, amino, C1-C6alkyl, _C2 -C6alkenyl, _C1 -C6alkoxy, C2C6alkynyl, _C2- C6alkanoyl, _C1 -C6thioalkyl, _hydroxyC1 - _C6 alkyl, aminoC ₁ -C6alkyl, -C ₀ -C ₄ alkyl-NR ⁹ R ¹⁰ , -C(O)OR ⁹ , -OC(O)R ⁹ , -NR ⁹ C(O)R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ , -NR ⁹ C(O)OR ¹⁰ , CrC2haloalkyl and C1C2haloalkoxy, where R ⁹ and R ¹⁰ are independently selected in each case from hydrogen, C1-C6alkyl and (C3C7cycloalkyl) _C0 -C ₄ -alkyl;

(d) -C ₀ -C ₄ alkyl(C ₃ -C ₇ cycloalkyl) and -O-C ₀ -C ₄ alkyl(C ₃ -C ₇ cycloalkyl).

In addition, any one of the following rings (e), (f), (g), (h), (i) or (j) may be present:

(e) R ¹ and R ¹ or R ³ and R ³ may be taken together to form a 3-6 membered carbocyclic spiro ring or a 3-6 membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N , O or S;

(f) R ² and R ^2' can be taken together to form a 3-6 membered carbocyclic spiro ring;

(g) R ² and R ^2' can be taken together to form a 3-6 membered heterocyclic spiro ring, each of the spiro rings (e), (f) and (g) being unsubstituted or substituted with one or more halogen or methyl substituents ;

(h) R ¹ and R ² can be taken together to form a 3-membered carbocyclic ring;

(i) R ¹ and R ² can be taken together to form a 4-6 membered carbocyclic ring or a 46 membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O and S;

(j) R ² and R ³ , when bonded to adjacent carbon atoms, can be taken together to form a 36-membered carbocyclic ring or a 3-6 membered heterocyclic ring; each ring (g), (h) and (i) may be unsubstituted or substituted with 1 or more substituents independently selected from halogen, hydroxyl, cyano, -COOH, C1- _C4 alkyl, _C2 - _C4 alkenyl, C1 -C ₄ alkoxy, C ₂ -C ₄ alkanoyl, hydroxyC _g C ₄ alkyl, (mono- and di-C ₁ -C ₄ alkylamino)C ₀ -C ₄ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -O-C ₀ C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C1-C ₂ haloalkyl and C1-C ₂ haloalkoxy.

A represents a heterocyclic group selected from (k) and (l), where (k) represents

(l) represents

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X ⁴ represents B(OH) and Y represents CHR ⁹ ; or X ⁴ is CHR ⁹ and Y is B (OH).

R ⁴ is (t) or (n):

(t) -CHO, -CONH ₂ or C ₂ -Sbalcanoyl;

(p) hydrogen, -SO ₂ NH ₂ , -C(CH ₂ )F, -CH(CF ₃ )NH ₂ , C1-C ₆ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -C(O)C ₀ C ₂ alkyl (C ₃ -C ₇ cycloalkyl),

each of R ⁴ other than hydrogen, -CHO and -CONH ₂ is unsubstituted or substituted by one or more of amino, imino, halogen, hydroxyl, cyano, cyanoimino, C1- _C2 alkyl, C1- _C2 alkoxy, -Co- C ₂ alkyl (mono- and di-C1-C ₄ alkylamino), C1-C ₂ haloalkyl and C1-C ₂ haloalkoxy.

R ⁵ and R ⁶ are independently selected from (o) and (p):

(o) -CHO, -C(O)NH ₂ , -C(O)NH(CH ₃ ) or C ₂ -C ₆ alkanoyl;

(p) hydrogen, hydroxyl, halogen, cyano, nitro, -COOH, -SO ₂ NH ₂ , vinyl, Ci-Sb-alkyl, C ₂ -Sbalkenyl, Ci-Sbalkoxy, -Co-C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -C(0)Co-C ₄ alkyl(C ₃ -C ₇ cycloalkyl), -P(O)(OR ⁹ )2, -OC(O)R ⁹ , -C(O)OR ⁹ , -C(O)N(CH2CH ₂ R ⁹ )(R ¹⁰ ), -NR ⁹ C(O)R ¹⁰ , phenyl or 5-6-membered heteroaryl.

Each R ⁵ and R ⁶ other than hydrogen, hydroxyl, cyano and -COOH is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, imino, cyano, cyanoimino, C1- _C2 alkyl, C1-C ₄ alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C1-C ₄ alkylamino), C1-C ₂ haloalkyl and C1-C ₂ haloalkoxy.

R ⁶ represents hydrogen, halogen, hydroxyl, C1- _C4 alkyl or C1- _C4 alkoxy; or R ⁶ and R ⁶ can be taken together to form an oxo, vinyl or imino group.

R ⁷ represents hydrogen, Ci-Svalkyl or -Co-C ₄ alkyl (C ₃ -C ₇ cycloalkyl.

R ⁸ and R ⁸ are independently selected from hydrogen, halogen, hydroxyl, Ci-Svalkyl, Ci-Cbalkoxy and (Cp C ₄ alkylamino)Co-C ₂ alkyl or R ⁸ and R ⁸ taken together form an oxo group.

R ¹⁶ represents 0 or 1 or more substituents independently selected from halogen, hydroxyl, nitro, cyano, Ci-Svalkyl, C ₂ -Sbalkenyl, C ₂ -Sbalkanol, Ci-Sbalkoxy, -Co-C ₄ alkyl(mono - and di-C1-Cbalkylamino), -Co-C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C1-C ₂ haloalkyl and C1-C ₂ haloalkoxy.

R ¹⁹ represents hydrogen, Ci-Sbalkyl, C2-Sbalkenyl, C2-Sbalkanoyl, -8O2C1-Svalkyl, (mono-di-C1-Sbalkylamino)C1-C4alkyl, -Co-C4alkyl(C3-C7cycloalkyl), each of ^R19 . other than hydrogen, is substituted with 0 or 1 or more substituents independently selected from halogen, hydroxyl, amino, -COOH and -C(O)OC1-C4-alkyl.

X ¹¹ represents N or CR ¹¹ .

X ¹² represents N or CR ¹² .

X ¹³ represents N or CR ¹³ .

X ¹⁴ represents N or CR ¹⁴ .

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X ¹⁵ represents N or CR ¹⁵ .

At most 2 of X ¹¹ , X ¹² , X ¹³ , X ¹⁴ and X ¹⁵ are N.

R ¹¹ , R ¹⁴ and R ¹⁵ are independently selected in each case from hydrogen, halogen, hydroxyl, nitro, cyano, -O(PO)(OR ⁹ )2, -(PO)(OR ⁹ )2, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkoxy, C1C ₆ thioalkyl, -C ₀ -C ₄ alkyl (mono- and di-C1-C ₆ alkylamino), -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -C ₀ C ₄ alkoxy (C ₃ -C ₇ cycloalkyl), C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

R ¹² and R ¹³ are independently selected from (q), (r) and (s):

(q) hydrogen, halogen, hydroxyl, nitro, cyano, amino, -COOH, C ₁ -C ₂ haloalkyl and C1C ₂ haloalkoxy;

(r) C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyloxy, -C(O)OR ⁹ , C1C6thioalkyl, -Co -C4alkyl-NR ⁹ R ^1O , -C(O)NR ⁹ R ¹⁰ , -SO2R ⁹ R ¹⁰ , -SO2NR9R ¹⁰ , -OC(O)R ⁹ and -C(NR ⁹ )NR ⁹ R ¹⁰ , each of ( r) is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, -COOH, -CONH2 C _{1 -C 2} haloalkyl and C ₁ -C ₂ haloalkoxy, and each of (r) is also optional substituted with one substituent selected from phenyl and a 4-7 membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein the phenyl or 4-7-membered heterocycle is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkoxy, (mono- and di-C ₁ -C ₆ alkylamino)C ₀ -C ₄ alkyl, C ₁ -C ₆ alkyl ether, -C ₀ -C ₄ alkyl)(C ₃ -C ₇ cycloalkyl), C1C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy;

(s) -C ₂ -C ₆ alkynyl, -C ₂ -C ₆ alkynyl-R ²³ , C2-C6alkanoyl, -JC3-C7cycloalkyl, -B(OH)2, -JC(O)NR ⁹ R ²³ , JOSO2OR ²¹ , -C(O)(CH2)1.4S(O)R ²¹ , -O(CH2)1.4S(O)NR ²¹ NR ²² , JOP(O)(OR ²¹ )(OR ²² ), -JP(O) (OR ²¹ )(OR ²² ), JOP(O)(OR ²¹ )R ²² , -JP(O)(OR ²¹ )R ²² , JOP(O)R ²¹ R ²² , -JP(O)R ²¹ R ²² , -JSP(O)(OR ²¹ )(OR ²² ), -JSP(O)(OR ²¹ )(R ²² ), JSP(O)(R ²¹ )(R ²² ), -JNR ⁹ P(O)( NHR ²¹ )(NHR ²² ), -JNR ⁹ P(O)(OR ²¹ )(NHR ²² ), -JNR ⁹ P(O)(OR ²¹ )(OR ²² ), -JC(S)R ²¹ , JNR ²¹ SO2R ²² , -JNR ⁹ S(O)NR ¹⁰ R ²² , -JNR ⁹ SO2NR ¹⁰ R ²² , -JSO2NR9COR ²² , -O(CH2)1- ₄ SO ₂ NR ²¹ R ²² , -

JSO2NR ⁹ CONR ²¹ R ²² , -JNR ²¹ SO2R ²² , -JC(O)NR ²¹ SO2R ²² , -JC(NH2)NR ²² , -JC(NH2)NS(O)2R ²² , JOC(O)NR ²¹ R ²² , -JOC(O)NR ²⁴ R ²⁵ , -JNR ⁹ C(O)OR ¹⁰ , -JNR ⁹ C(O)OR ²³ , -JNR ²¹ OC(O)R ²² , -(CH2)1.4C(O )NR ²¹ R ²² , -JC(O)R ²⁴ R ²⁵ , -JNR ⁹ C(O)R ²¹ , -JC(O)R ²¹ , -JNR ⁹ C(O)NR ⁹ R ¹⁰ , -JNR ⁹ C (O)NR ¹⁰ R ²³ , -JNR ⁹ C(O)NR ²⁴ R ²⁵ , -CCR ²¹ , (CH2)1-4OC(O)R ²¹ , -JC(O)OR ²³ , -C2-C ₄ alkyl -R ²³ , -C2-C4alkenyl-R ²³ , -C2-C ₄ alkynyl-R ²³ and -J-paracyclophane.

J is independently selected in each case from a covalent bond, C1- _C4 alkylene, _-OC1 - _C4 alkylene, C2C4alkenylene, and _C2 -C4alkynylene.

R ²¹ and R ²² are independently selected in each case from hydrogen, hydroxyl, cyano, amino, C ₁ C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, (C ₃ -C ₇ cycloalkyl)C ₀ - C ₄ alkyl, (phenyl)C ₀ -C ₄ alkyl, -C1-C ₄ alkylOC(O)OC ₁ -C ₆ alkyl, -C ₁ -C ₄ alkyl-OC(O)C ₁ -C ₆ -alkyl, -C ₁ -C ₄ alkylC(O)OS ₁ -C ₆ alkyl, (4-7 membered heterocycloalkyl)C ₀ -C ₄ alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S, and (5 or 6 membered unsaturated or aromatic heterocycle) C ₀ -C ₄ -alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S.

R ²³ is independently selected in each case from (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ -alkyl, (phenyl)C ₀ -C ₄ -alkyl, (4-7-membered heterocycloalkyl)C0-C4 alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S, and (5- or 6-membered unsaturated or aromatic heterocycle) C ₀ -C ₄ alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S .

R ²⁴ and R ²⁵ , taken together with the nitrogen atom to which they are attached, 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 (s) may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH) ₂ , -Si( _CH3 ) ₃ , -COOH, CONH2, -P(O)(OH) ₂ , C ₁ -C ₆ alkyl, C1-C ₆ alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C1-C ₄ alkylamino), C1C ₆ alkyl ether, C1-C ₄ alkylamino, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

L represents either (t), (u), or (v):

(t) represents a group of the formula wherein R ¹⁷ represents hydrogen or C ₁ -C ₆ alkyl, and R ¹⁸ and R ¹⁸ are independently selected from hydrogen, halogen and methyl; and m is 0,1,2 or 3; and (u) represents a connection;

(v) or a group of formula

N

N or

B represents a monocyclic or bicyclic carbocyclic or carbocyclic-hydroxy 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 represents a C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl group.

Each of B is unsubstituted or substituted with one or more substituents independently selected from (w) and (x), and 0 or 1 substituent selected from (y) and (z):

(w) halogen, hydroxyl, -COOH, cyano, C ₁ -C ₆ αlkyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkoxy, -C ₀ -C ₄ alkylNR ⁹ R ¹⁰ , -SO2R ⁹ , C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy;

(x) nitro, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ thioalkyl, -JC ₃ -C ₇ cycloalkyl, -B(OH) ₂ , -JC(O)NR ⁹ R ²³ , JOSO2OR ²¹ , -C(O)(CH2)1-4S(O)R ²¹ , -O(CH2)1-4S(O)NR ²¹ R ²² , -JOP(O)(OR ²¹ )(OR ²² ) , -JP(O)(OR ²¹ )(OR ²² ), JOP(O)(OR ²¹ )R ²² , -JP(O)(OR ²¹ )R ²² , JOP(O)R ²¹ R ²² , -JP( O)R ²¹ R ²² , -JSP(O)(OR ²¹ )(R ²² ), -JSP(O)(OR ²¹ )(R ²² ), JSP(O)(R ²¹ )(R ²² ), -JNR ⁹ P(O)(NHR ²¹ )(NHR ²² ), -JNR ⁹ P(O)(OR ²¹ )(NHR ²² ), -JNR ⁹ P(O)(OR ²¹ )(OR ²² ), -JC(S )R ²¹ , JNR21SO2R ²² , -JNR ⁹ S(O)NR ¹⁰ R ²² , -jnr ⁹ so2nr ¹⁰ r ²² , -jso2nr ⁹ cor ²² , -jso2nr ⁹ conr ²¹ r ²² , -jnr ²¹ so2r ²² , JC(O )NR ²¹ SO2R ²² , -JC(NH2)NR ²² , -JC(NH2)NS(O)2R ²² , -JOC(O)NR ²¹ R ²² , -JNR ²¹ C(O)OR ²² , -JNR ²¹ OC (O)R ²² , (CH2)1-4C(O)NR ²¹ R ²² , -JC(O)R ²⁴ R ²⁵ , -JNR ⁹ C(O)R ²¹ , -JC(O)R ²¹ , -JNR ⁹ C(O)NR ¹⁰ R ²² , -CCR ²¹ , -(CH2)14OC(O)R ²¹ and -JC(O)OR ²³ ; each of (x) may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH)2, Si( _CH3 ) ₃ , -COOH, -CONH2, -P(O)(OH) ₂ , C ₁ -C ₆ αlkyl, C ₁ -C ₆ alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C ₁ C ₄ alkylamino), C ₁ -C ₆ alkyl ether , C1-C ₄ alkylamino, C1-C ₄ hydroxyalkyl, C ₁ -C ₂ haloalkyl and C1C ₂ haloalkoxy;

(y) naphthyl, naphthyloxy, indanyl, (4-7-membered heterocycloalkyl)C ₀ -C ₄ alkyl containing 1 or 2 heteroatoms selected from N, O and S, and a bicyclic heterocycle containing 1, 2 or 3 heteroatoms, independently selected from N, O and S, and containing from 4 to 7 ring atoms in each ring; each of (y) is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ αlkoxy, (mono- and di-C ₁ -C ₆ alkylamino)C ₀ -C ₄ alkyl, C ₁ -C ₆ αlkyl ether, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -SO2R ⁹ , C1C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy; and (z) tetrazolyl, (phenyl)C ₀ -C ₂ alkyl, (phenyl)C ₁ -C ₂ alkoxy, phenoxy and 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O , B and S, each of (z) unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkoxy, (mono- and di-C ₁ C ₆ alkylamino) C ₀ -C ₄ alkyl, C ₁ -C ₆ alkyl ether, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), - SO2R ⁹

-OSi(CH ₃ ) ₂ C(CH ₃ ) ₃ , Si(CH ₃ ) ₂ C(CH ₃ ) ₃ , C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

Either X ² is nitrogen or at least one of (d), (e), (g), (i), (l), (n), (p), (s), (v), (x) and (y) are present. Also disclosed is a pharmaceutical composition containing a compound or salt of Formula I together with a pharmaceutically acceptable carrier.

Also disclosed are methods of treating or preventing disorders mediated by the complement factor D cascade, such as age-related macular degeneration and retinal degeneration, comprising administering a therapeutically effective amount of a compound or salt of Formula I to a patient in need of such treatment.

Priority document terminology

Connections are described using standard nomenclature. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention belongs. Unless clearly inconsistent with the context, each compound name includes the free acid or free base form of the compound, as well as all pharmaceutically acceptable salts of the compound.

The term formula I covers all compounds that satisfy formula I, including any enantiomers, racemates and stereoisomers, as well as all pharmaceutically acceptable salts of these compounds. formula I includes all subgeneric groups of formula I, such as formula IA and IB, and also includes pharmaceutically acceptable salts of the compounds of formula I, unless clearly inconsistent with the context in which this phrase is used.

The singular number does not mean a limitation in quantity, but rather indicates the presence of at least one of what is described. The term or means both/or. An open transition phrase containing covers an intermediate transition phrase consisting essentially of and a closed phrase consisting of. Claims made by one of these three transitional phrases, or an alternative transitional phrase such as containing or including, may be expressed by any other transitional phrase unless clearly precluded by the context or art. The indication of ranges of values is intended only as a shorthand way of referring individually to each individual value falling within the range, unless otherwise specified herein, and each individual value is included in the description as if it were individually stated herein. The ends of all ranges are included within the range and are independently combined. All methods described herein may be performed in an appropriate order unless otherwise stated herein or otherwise clearly contrary to the context. The use of any or all examples or illustrative expressions (eg, such) is intended to better illustrate the invention only and is not intended to limit the scope of the invention unless otherwise stated. Nothing in the specification should be construed as indicating any element not claimed as essential to the practice of the invention as used herein. Unless otherwise specified, technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention belongs.

Compounds of formula I include all compounds of formula I having isotopic substitutions at any position. Isotopes include those atoms that have the same atomic number but different mass numbers. By general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ^nC , ^13C , and ^14C . Although compounds of Formula I require moderate to high levels of deuteration (substitution of deuterium for hydrogen) at certain positions, Formula I includes includes embodiments in which other positions are enriched with isotopes.

Active agent means a compound (including a compound described herein), element or mixture that, when administered to a patient alone or in combination with another compound, element or mixture, results directly or indirectly in a physiological effect in the patient. An indirect physiological effect may occur through a metabolic or other indirect mechanism.

A bar (-) that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -(C=O)NH2 is attached through the carbon of the keto (C=O) group.

Alkyl is a branched or straight saturated aliphatic hydrocarbon group having a specific number of carbon atoms, typically from 1 to about 12 carbon atoms. The term C ₁ -C ₆ αlkyl as used herein indicates an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. Other embodiments include alkyl groups having 1 to 8 carbon atoms, 1 to 4 carbon atoms, or 1 or 2 carbon atoms, for example, C ₁ -C ₈ alkyl, C 1 -C ₄ alkyl, and C ₁ -C ₂ alkyl. When _C0 - _Cn alkyl is used herein in combination with another group, for example, _{( C3} -C7cycloalkyl) _C0 - _C4alkyl or _-C0 - _C4alkyl ( _{C3C7cycloalkyl} ), then the group , in this case cycloalkyl, is either directly linked by a single covalent bond (C ₀ alkyl), or attached by an alkyl chain having a specified number of carbon atoms, in this case 1, 2, 3 or 4 carbon atoms. Alkyls can also be attached through other groups such as heteroatoms, as in -O-C ₀ -C ₄ αlkyl(C ₃ -C ₇ cycloalkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t-butyl, npentyl and sec-pentyl.

Alkenyl is a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds that can occur at any stable point on a chain having a specified number of carbon atoms. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.

Alkynyl is a straight or branched aliphatic hydrocarbon group having one or more double carbon-carbon triple bonds that can occur at any stable point on a chain having a specified number of carbon atoms.

Alkylene means a divalent saturated hydrocarbon. Alkylenes include groups having from 1 to 8 carbon atoms, from 1 to 6 carbon atoms, or a specified number of carbon atoms, for example, C1-C4 alkylene.

Alkenylene is a divalent hydrocarbon having at least one carbon-carbon double bond. Alkenylenes include groups having from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or a specified number of carbon atoms, for example, C2-C4 alkenylene.

Alkynylene is a divalent hydrocarbon having at least one carbon-carbon triple bond. Alkynylenes include groups having from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or a specified number of carbon atoms, for example, C ₂ -C ₄ alkynylene.

Alkoxy means an alkyl group, as defined above, with the specified number of carbon atoms covalently bonded to the group it replaces via an oxygen bridge (-O-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n- hexoxy, 2-hexoxy, 3hexoxy and 3-methylpentoxy. Similarly, an alkylthio or ioalkyl group is an alkyl group, as defined above, of the specified number of carbon atoms, covalently linked to the group it replaces via a sulfur bridge (-S-).

Alkenyloxy is an alkenyl group, as defined above, with the specified number of carbon atoms, covalently linked to the group it replaces via an oxygen bridge (-O-).

An alkanoyl is an alkyl group, as defined above, with a specified number of carbon atoms, covalently linked to the group it replaces via a carbonyl bridge

- 194 043505 (C=O). The carbon of the carbonyl group is one of the carbon atoms, that is, C2alkanoyl is a CH ₃ (C=O)- group.

An alkyl ether is an alkyl group, as defined herein, covalently linked to the group it replaces via an ester bond. The ester bond can be in one orientation or another, for example, a group with the formula -O(C=O)alkyl or a group with the formula -(C=O)Oalkyl.

A carbocyclic group is a saturated, unsaturated or partially unsaturated (eg, aromatic) group containing all carbon ring atoms. A carbocyclic group typically contains 1 ring with 3 to 7 carbon atoms or 2 fused rings, each containing 3 to 7 carbon atoms. A carbocyclic ring is a saturated, unsaturated, or partially unsaturated (eg, aromatic) ring containing 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.

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

Cycloalkyl is a saturated hydrocarbon ring group having a specific number of carbon atoms. Monocyclic cycloalkyl groups typically have from 3 to about 8 carbon atoms in the ring or from 3 to 7 (3, 4, 5, 6 or 7) carbon atoms in the ring. The cycloalkyl substituents may be pendant from a substituted nitrogen atom or a carbon atom, or the substituted carbon atom, which may have two substituents, may have a cycloalkyl group that is attached as a spiro group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

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

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

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

Aminoalkyl is an alkyl group, as previously described, substituted with at least one amino substituent. A halo or halogen is any of fluorine, chlorine, bromine and iodine atoms.

Aryl are aromatic groups containing only carbon in the aromatic ring or rings. Typical aryl groups contain from 1 to 3 separate, fused or pendant rings and from 6 to about 18 ring atoms, with no heteroatom as a ring member. When indicated, such aryl groups may be further substituted with carbon atoms or non-carbon atoms or groups. Such substitution may involve condensation with a 5 to 7 membered saturated cyclic group, which optionally contains 1 or 2 heteroatoms independently selected from N, O and S, to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl, naphthyl, including 1-naphthyl and 2-naphthyl, and biphenyl.

A heterocyclic ring is a saturated, unsaturated, or partially unsaturated (e.g., aromatic) ring containing from 1 to 4 heteroatoms per ring, independently selected from N, O, and S, or, if indicated, N, O, S, and B, with the remaining carbons ring atoms. A heterocyclic group may contain 1 heterocyclic ring, 1 ring with 3 to 7 ring atoms, or 2 fused rings, each containing 3 to 7 ring atoms, with at least one ring that is a heterocyclic ring.

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

Heteroaryl is a stable monocyclic aromatic ring containing a specified number of ring atoms, which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms selected from N, O and S, the remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5 to 7 membered aromatic ring containing from 1 to 3, or in some embodiments from 1 to 2 heteroatoms selected from N, O and S, the remaining ring the atoms are carbon. Monocyclic heteroaryl groups typically have 5 to 7 ring atoms. In some embodiments, the 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-membered aromatic ring is fused to a second aromatic ring. or a non-aromatic ring. When the total number of S and O atoms in a heteroaryl group exceeds 1, the heteroatoms are not adjacent to each other. It is preferable that the total number of S and O atoms in the heteroaryl group is not more than 2. It is especially preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not limited to, oxazolyl, pyranyl, pyrazinyl, pyrazolopyrimidinyl, pyrazolyl, pyridizinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienylpyrazolyl, thiophenyl, triazolyl, benzo[d]oxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxadiazolyl, dihydrobenzodioxinyl, furanyl, imidazolyl, indolyl and isoxazolyl. Heteroaryloxy is a heteroaryl group as described linked to the group it replaces via an oxygen bridge.

Heterocycloalkyl is a saturated ring group having 1,2,3 or 4 heteroatoms independently selected from N, S and O, the remaining ring atoms being carbon. Monocyclic heterocycloalkyl groups typically have 3 to 8 ring atoms or 4 to 6 ring atoms. Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl and pyrrolinyl.

The term mono- and/or dialkylamino indicates secondary or tertiary alkylamino groups, wherein the alkyl groups are independently selected from alkyl groups as defined herein containing the specified number of carbon atoms. The point of attachment of the alkylamino group is at nitrogen. Examples of mono- and dialkylamino groups include ethylamino, dimethylamino and methylpropylamino.

The term substituted, as used herein, means that any one or more hydrogen atoms on a specified atom or group are replaced by one selected from the specified group, provided that the normal valence of the specified atom is not exceeded. When the substituent is oxo (i.e. =O), then 2 hydrogen atoms per atom are replaced. When an oxo group is replaced by aromatic moieties, the corresponding partially unsaturated ring replaces the aromatic ring. For example, a pyridyl group substituted with an oxo group is pyridone.

Combinations of substituents and/or variables are permitted only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure means a compound that is stable enough to withstand isolation from the reaction mixture and subsequent processing into an effective therapeutic agent. Unless otherwise noted, substituents are named in the main structure. For example, it should be understood that when aminoalkyl is indicated as a possible substituent, the point of attachment of this substituent to the core structure is at the alkyl moiety.

Suitable groups that may be present at the substituted or optionally substituted position include, but are not limited to, for example, halogen; cyano; hydroxyl; nitro; azido; alkanoyl (including a C ₂ -C ₆ αalkanoyl group); carboxamide; alkyl groups (including cycloalkyl groups) having from 1 to about 8 carbon atoms or from 1 to about 6 carbon atoms; alkenyl and alkynyl groups, including groups having one or more unsaturated bonds and from 2 to about 8 or from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen bonding 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 1 to 8 carbon atoms or 1 to 6 carbon atoms; alkylsulfinyl groups, including those having one or more sulfinyl linkages and from 1 to about 8 carbon atoms or from 1 to about 6 carbon atoms; an alkylsulfonyl group, including one having one or more sulfonyl linkages and from 1 to about 8 carbon atoms or from 1 to about 6 carbon atoms; aminoalkyl groups, including groups having one or more N atoms and 1 to about 8 or 1 to about 6 carbon atoms; aryl containing 6 or more carbon atoms and one or more rings (eg, phenyl, biphenyl, naphthyl or the like, each ring being either substituted or unsubstituted aromatic); arylalkyl having from 1 to 3 separate or fused rings and from 6 to about 18 carbon atoms in the ring with benzyl being an example of an arylalkyl group; arylalkoxy having from 1 to 3 separate or fused rings and from 6 to about 18 carbon atoms in the ring with benzyloxy being an example of an arylalkoxy group; or a saturated, unsaturated or aromatic heterocyclic group having from 1 to 3 separate or fused rings with from 3 to about 8 ring members and one or more N, O or S atoms, for example, coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl and pyrrolidinyl. Such heterocyclic groups may be further substituted, for example, with hydroxy, alkyl, alkoxy, halogen and amino. In some embodiments, optionally substituted includes one or more substituents independently selected from halogen, hydroxyl, amino, cyano, -CHO, -COOH,

- 196 043505

-CONH2, C ₁ -C ₆ -alkyl, C ₂ -C ₆ alkenyl, C1-Cbalkoxy, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ αlkyl ether, (mono- and di-C1Cbalkylamino)Co-C2alkyl, C1- C ₂ haloalkyl and C1-C ₂ haloalkoxy.

Dosage form means a unit of administration of the active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, solutions, emulsions, creams, ointments, suppositories, inhalation forms, transdermal forms, and the like.

Pharmaceutical compositions are compositions containing at least one active agent, such as a compound or salt of Formula I, and at least one other substance, such as a carrier. The pharmaceutical compositions optionally contain one or more additional active agents. Where indicated, the pharmaceutical compositions meet U.S. standards. FDA's GMP (Good Manufacturing Practices) for human and non-human drugs. Pharmaceutical combinations are combinations of at least two active agents that may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat a disease such as hepatitis C.

The term pharmaceutically acceptable salts includes derivatives of the disclosed compounds in which the parent compound is modified by the formation of inorganic and organic non-toxic acid or basic addition salts. Salts of the compounds of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the corresponding base (e.g., Na, Ca, Mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base form of these compounds with stoichiometric amount of the corresponding acid. Such reactions are usually carried out in water, or an organic solvent, or a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred where practical. Salts of the compounds of the present invention further include solvates of the compounds and compound salts.

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

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

The term pharmaceutically acceptable excipient means an excipient that is suitable for the preparation of a pharmaceutical composition/combination that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for use in veterinary medicine as well as pharmaceutical purposes for humans. A pharmaceutically acceptable excipient, as used herein, includes one or more such excipients.

The patient is a human or non-human animal in need of medical treatment. Medical treatment may include treatment of an existing condition such as a disease or disorder, prophylactic or preventive treatment, or diagnostic treatment. In some embodiments of the invention, the patient is a human patient.

Providing means supplying, introducing, selling, distributing, transferring (whether for profit or not), manufacturing, compounding or dispersing.

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 simultaneously in separate dosage forms, or provided in separate dosage forms for administration separated by a period of time , which is the time interval in which the compound of formula I and at least one additional active agent is in the blood stream of the patient. In some embodiments

- 197 043505 of the invention, the compound of formula I and the additional active agent do not have to be prescribed to the patient by the same health care provider. In some embodiments, the additional active agent or agents do not require a prescription. Administration of a compound of formula I or at least one additional active agent can occur by any suitable route, for example, oral tablets, oral capsules, oral solutions, inhalation, injection, suppository or local contact.

Treatment, as used herein, involves providing a compound of Formula I, either as a single active agent or together with at least one additional active agent, sufficient to: (a) prevent a disease or symptom of a disease in a patient who may be susceptible to to a disease but not yet known to be susceptible to it (for example, including diseases that may be associated with or caused by a primary disease (as in macular degeneration, which may result in the context of factor D activation); (b) inhibit disease, i.e., delay its progression, and (c) ameliorate the disease, i.e., cause regression of the disease.The terms treat and treat also mean providing a therapeutically effective amount of a compound of formula I as the sole active agent or together with at least one an additional active agent to a patient who has or is susceptible to a complement factor D-mediated condition.

The term therapeutically effective amount of a pharmaceutical composition/combination of the present invention means an amount effective when administered to a patient to provide a therapeutic benefit such as improvement of symptoms, for example, an amount effective to reduce symptoms of macular degeneration. A therapeutically effective amount is also an amount sufficient to prevent a significant increase or significant decrease in the detectable level of complement factor D in the blood, serum or tissues of the patient.

Chemical description.

In addition to the compounds of formula I given in the Summary of the Invention, the present invention also includes compounds in which the variables, for example, A, B, L, R1-R ³ and L have the following definitions. The description includes all combinations of these definitions resulting in stable compounds.

For example, the disclosure includes compounds and salts of formulas II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI and XXII, which are included in the scope of Formula I. The variables specified in Formulas II-XXIV have the definitions set forth in the Summary of the Invention for Formula I or any of the definitions set forth in the present description.

- 198 043505

- 199 043505

Formula XIX

Formula XVII

w is 0 or 1.

Formula XVIII

Formula XXI

Formula XX

Formula XXIII Formula XXIV

In addition, the invention includes compounds and salts of formula I and any of its subformulas (II-XXIV), in which at least one of the following conditions is satisfied.

R ¹ , R ¹ , R ² , R ³ and R ³ , if present, are all hydrogen; and R ² is fluorine.

R ¹ , R ¹ , R ² and R ³ , if present, are all hydrogen; and R ² represents fluorine and R ³ represents -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl) or -O-C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl.

R ¹ and R ² taken together 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 , if present, are all hydrogen, and R ² and R ² taken together form a 5- or 6-membered heterocycloalkyl group having 1 or 2 oxygen atoms.

-L-B- represents

R ²⁶ and R ²⁷ are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ alkyl, C ₂ C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkyl, -C ₀ -C ₄ alkyl (mono- and di-C1-C ₆ alkylamino), -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -C ₀ -C ₄ alkoxy- (C ₃ - C ₇ cycloalkyl), C ₁ -C ₂ haloalkyl, C 1 -C ₂ haloalkoxy and C ₁ -C ₂ haloalkylthio.

(f -L-B- represents

- 200 043505

or ^r 25 ; Where

R ¹⁸ and R ¹⁸ are independently selected from hydrogen, halogen and methyl; and m is 0 or 1; And

R ²⁶ , R ²⁷ and R ²⁸ are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, €1-C6alkoxy, C1-C6thioalkyl, (mono- and di-C1- C6alkylamino)C0C4alkyl, (C3-C7cycloalkyl)C0-C4alkyl and -C0-C4alkoxy(C3-C7cycloalkyl); each of R ²⁶ , R ²⁷ and R ²⁸ other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, C1C2alkoxy, _C1 - _C2 haloalkyl and C ₁ -C ₂ haloalkoxy; And

R ²⁹ represents hydrogen, C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl or Si(CH ₃ ) ₂ C(CH ₃ ) ₃ ;

(g) R ⁸ and R ⁸ are independently hydrogen or methyl;

(h) R ⁸ and R ⁸ are hydrogen;

(i) R ⁷ is hydrogen or methyl;

(j) R ⁷ is hydrogen.

(k) One of R ¹² and R ¹³ is selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkyl, -C ₀ -C ₄ alkyl (mono- and di-C1C ₆ alkylamino), -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -OC ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C ₂ haloalkyl and C 1 -C ₂ haloalkoxy;

(l) R ¹ , R ¹ , R ² and R ³ are all hydrogen;

R ² represents fluorine and R ³ represents hydrogen, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl) or O-C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl);

R ⁵ represents hydrogen, halogen or C ₁ -C ₂ alkyl;

R ¹¹ , R ¹³ R ¹⁴ and R ¹⁵ , if present, are independently selected in each case from hydrogen, halogen, hydroxyl, amino, C 1 -C ₄ alkyl, C 1 -C ₄ alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C ₁ -C ₂ alkylamino), trifluoromethyl and trifluoromethoxy;

X ¹² represents CR ¹² ; And

R ¹² represents -JNR ⁹ C(O)OR ¹⁰ , -JNR ⁹ C(O)OR ²³ , -JOC(O)NR ²¹ R ²² , -JOC(O)NR ²⁴ R ²⁵ , -JNR ⁹ C(O )NR ¹⁰ R ²³ or -JNR ⁹ C(O)NR ²⁴ R ²⁵ ;

(m) J represents a bond.

(n) One of R ¹² and R ¹³ is selected from

- 201 043505

where p is 0, 1, 2, 3 or 4.

(o) Disclosure includes compounds and salts of Formula VII

^R2 . , ^R3

R ² -V4, ^B rI^N O ^κ k Ju r ¹³

R ^5- Jj T rv^R ^{12 r6} R ¹¹ (VII), where:

R ¹ , R ² , R ² and R ³ are independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, -C0-C2 alkylNR9R ¹⁰ , -C0-C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -O- C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl, C ₁ -C ₂ haloalkyl and C ₁ C ₂ haloalkoxy;

R8 and R8 are independently selected from hydrogen, halogen and methyl;

R ⁵ represents hydrogen, hydroxyl, cyano, -COOH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ C ₆ alkanoyl -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -C (O)C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl, C ₁ -C ₂ haloalkyl or C ₁ -C ₂ haloalkoxy;

R ⁶ is -C(O)CH ₃ , -C(O)NH ₂ , -C(O)CF ₃ , -C(O)(cyclopropyl) or -ethyl(cyanoimino);

And

R ¹¹ and R ¹⁴ are independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkyl, -C ₀ -C ₄ alkyl (mono- and di-C ₁ C ₆ alkylamino), -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -OC ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

(p) B selected from

- 202 043505

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

(q) B is phenyl, pyridyl or indanyl, each of which is unsubstituted or substituted with one or more substituents independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkyl, (mono- and di-C1C ₆ alkylamino)C ₀ -C ₄ alkyl, (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl, -C ₀ -C ₄ alkoxy (C ₃ -C ₇ cycloalkyl), (phenyl)C ₀ -C ₂ alkyl, (pyridyl)C ₀ -C ₂ alkyl; each of the substituents other than hydrogen, halogen, hydroxyl, nitro, cyano is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxyl, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, -OSi (CH ₃ ) ₂ C(CH ₃ ) ₃ , -Si(CH ₃ ) ₂ C(CH ₃ ) ₃ , C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

(r) B is phenyl or pyridyl substituted with 1, 2 or 3 substituents selected from chloro, bromine, hydroxyl, -SCF3, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, trifluoromethyl and trifluoromethoxy.

(s) A represents a group of the formula

(t)-L-B represents a bond and an indanyl group of the formula

The present invention further includes embodiments of the invention in which m is 0 or 1;

R ² is halogen, R ² is hydrogen or halogen, and R ³ is hydrogen, halogen, -C ₀ -C ₄ alkyl(C ₃ -C ₇ cycloalkyl) or -O-C ₀ -C ₄ alkyl(C ₃ -C ₇ cycloalkyl;

R ⁶ represents -C(O)C1-C ₄ alkyl, -C(O)NH ₂ , -C(O)CF ₃ , -C(O)(C ₃ -C ₇ cycloalkyl) or -ethyl(cyanoimino) ;

one of R ¹² and R ¹³ is selected from hydrogen, halogen, C1- _C4 alkyl, C1- _C4 alkoxy, trifluoromethyl and trifluoromethoxy; the other of R ¹² and R ¹³ is selected from (s);

where (s) represents C ₂ -C ₆ alkynyl, -C ₂ -C ₆ alkynyl-R ²³ , C2-C6alkanoyl, -JC3-C7cycloalkyl, -B(OH)2, -JC(O)NR ⁹ R ²³ , -JOSO2OR ²¹ , -C(O)(CH2) _1-4 S(O)R ²¹ , -O(CH ₂ ) _1-4 S(O)NR ²¹ NR ²² , -JOP(O)(OR ²¹ )( OR ²² ), -JP(O)(OR ²¹ )(OR ²² ), -JOP(O)(OR ²¹ )R ²² , JP(O)(OR ²¹ )R ²² , -JOP(O)R ²¹ R ²² , -JP(O)R ²¹ R ²² , -JSP(O)(OR ²¹ )(OR ²² ), -JSP(O)(OR ²¹ )(R ²² ), -JSP(O)(R ²¹ )(R ²² ), -JNR ⁹ P(O)(NHR ²¹ )(NHR ²² ), -JNR ⁹ P(O)(OR ²¹ )(NHR ²² ),

JNR ⁹ P(O)(OR ²¹ )(OR ²² ), -JC(S)R ²¹ , -JNR ²¹ SO2R ²² , -JNR ⁹ S(O)NR ¹⁰ R ²² , JNR ⁹ SO2NR ¹⁰ R ²² , -JSO2NR ⁹ COR ²² , -O(CH2)1-4SO2NR ²¹ R ²² , -JSO2NR ⁹ CONR ²¹ R ²² , -JNR ²¹ SO2R ²² , JC(O)NR ²¹ SO2R ²² , -JC(NH2)NCN, -JC(NH2 )NR ²² , -JC(NH2)NS(O) ₂ R ²² , -JOC(O)NR ²¹ R ²² , -JOC(O)NR ²⁴ R ²⁵ , -JNR ⁹ C(O)OR ¹⁰ , -JNR ⁹ C(O)OR ²³ , -JNR ²¹ OC(O)R ²² , -(CH2)1-4C(O)NR ²¹ R ²² , -JNR ⁹ C(O)R ²¹ , -JC(O)R ²¹ , -JNR ⁹ C(O)NR ⁹ R ¹⁰ , -JNR ⁹ C(O)NR ¹⁰ R ²³ , -JNR ⁹ C(O)NR ²⁴ R ²⁵ , -CCR ²¹ , -(CH2) _1-4 OC(O )R ²¹ , -JC(O)OR ²³ , -C2-C4alkyl-R ²³ and -J-paracyclophane; where J is independently selected in each case and represents a covalent bond, C1-C4alkylene, C2C4alkenylene or _C2 - _C4 alkynylene;

R ²¹ and R ²² are independently selected in each case from hydrogen, hydroxyl, cyano, amino, C ₁ C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, (C ₃ -C ₇ cycloalkyl)C ₀ - C ₄ alkyl, (phenyl)C ₀ -C ₄ alkyl, -C1-C ₄ alkyl- 203 043505

OS(O)OC1-Sbalkyl, -C ₁ -C ₄ alkylOC(O)C ₁ -C ₆ alkyl, -C ₁ -C ₄ αlkylC(O)OS ₁ -C ₆ alkyl, (4-7-membered heterocycloalkyl) C ₀ -C ₄ alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S, and (5 or 6 membered unsaturated or aromatic heterocycloalkyl)C ₀ -C ₄ -alkyl having 1, 2 or 3 heteroatoms , independently selected from N, O and S;

R ²³ is independently selected in each case from (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl, (phenyl)C ₀ -C ₄ alkyl, (47-membered heterocycloalkyl)C ₀ -C ₄ alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C ₀ -C ₄ alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S;

R ²⁴ and R ²⁵ , taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered monocyclic heterocycloalkyl group or a 6-10-membered bicyclic heterocycloalkyl group having fused, spiro or bridged rings; each of (s) may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH) ₂ , -Si(CH ₃ ) ₃ , -COOH, -CONH2 , -P(O)(OH) ₂ , C ₁ -C ₆ alkyl, CiC ₆ alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C1-C ₄ alkylamino), C ₁ -C ₆ αlkyl ether, C1 -C ₄ alkylamino, C 1 C ₄ hydroxyalkyl, C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

(r) The present invention includes compounds and salts in which one of R ¹² and R ¹³ represents hydrogen, hydroxyl, halogen, methyl or methoxy; and the other

R ¹² and R ¹³ are independently selected from (s), where (s) represents C ₂ -C ₆ alkynyl, -C ₂ -C ₆ alkynyl-R ²³ , C2-C6alkanoyl, -JC3-C7Cycloalkyl, -JC(O) NR ⁹ R ²³ , -C(O)(CH2)1-4S(O)R ²¹ , -JP(O)(OR ²¹ )(OR ²² ),

-JOP(O)(OR ²¹ )R ²² , -JP(O)(OR ²¹ )R ²² , -JOP(O)R ²¹ R ²² , -JP(O)R ²¹ R ²² , -JNR21SO2R ²² , -JNR21SO2R ²² , -JC(O)NR ²¹ SO2R ²² , -JC(NH2)NCN, -JC(NH2)NR ²² , -JC(NH2)NS(O)2R ²² , -JOC(O)NR ²¹ R ²² , - JOC(O)NR ²⁴ R ²⁵ , -JNR ⁹ C(O)OR ¹⁰ , -JNR ⁹ C(O)OR ²³ , -JNR ²¹ OC(O)R ²² , -JC(O)R ²¹ , -JNR ⁹ C(O)NR ⁹ R ¹⁰ , -JNR ⁹ C(O)NR ¹⁰ R ²³ , -JNR ⁹ C(O)NR ²⁴ R ²⁵ and -J-paracyclophane; where J is independently selected in each case and represents a covalent bond, C1-C4alkylene, C2-C4alkenylene or C2-C4alkynylene;

R ²¹ and R ²² are independently selected in each case from hydrogen, hydroxyl, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl, (phenyl)C ₀ -C ₄ alkyl, -C ₁ -C ₄ alkylOC(O)OS ₁ C ₆ alkyl, -C1-C ₄ alkylOC(O)C1-C ₆ -alkyl, -C ₁ -C ₄ alkylC(O)OS ₁ -C ₆ alkyl, (pyrrolidinyl)C ₀ -C ₄ alkyl, ((morpholinyl)C ₀ -C ₄ alkyl, (thiomorpholinyl)C ₀ -C ₄ alkyl, (piperidinyl)C ₀ -C ₄ alkyl, (piperazinyl)C ₀ C ₄ alkyl, (tetrahydrofuranyl)C ₀ -C ₄ alkyl, pyrazolyl)C ₀ -C ₄ alkyl, (thiazolyl)C ₀ -C ₄ alkyl, (triazolyl)C ₀ -C ₄ alkyl, (tetrazolyl)C ₀ -C ₄ alkyl, (imidazolyl)C ₀ -C ₄ alkyl, (oxazolyl)C ₀ -C ₄ alkyl, (furanyl)C ₀ -C ₄ alkyl, (pyridinyl)C ₀ -C ₄ alkyl, (pyrimidinyl)C ₀ -C ₄ alkyl, (pyrazinyl)C ₀ -C ₄ alkyl, (pyridizinyl)C0-C4 alkyl and (tetrahydropyridinyl)C0-C4 alkyl;

R ²³ is independently selected in each case from (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl, (phenyl)C ₀ -C ₄ alkyl, (pyrrolidinyl)C0-C4 alkyl, (morpholinyl)C0-C4 alkyl, (thiomorpholinyl) C0-C4alkyl, (piperidinyl)C0C4alkyl, (piperazinyl)C0-C4alkyl, (tetrahydrofuranyl)C0-C4alkyl, (pyrazolyl)C0-C4alkyl, (thiazolyl)C0-C4alkyl, (triazolyl)C0-C4alkyl, (tetrazolyl)C0-C4alkyl , (imidazolyl)C0-C4alkyl, (oxazolyl)C0-C4alkyl, (furanyl)C0-C4alkyl, (pyridinyl)C0-C4alkyl, (pyrimidinyl)C0-C4alkyal, (pyrazinyl) _C0 - _C4alkyl , (pyridizinyl)C ₀ -C ₄ alkyl and (tetrahydropyridinyl)C ₀ -C ₄ alkyl;

R ²⁴ and R ²⁵ , taken together with the nitrogen atom to which they are attached, form a pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl group, each of which is optionally bridged with a methylene or ethylene group or spiro with a C ₃ C ₆ cycloalkyl group;

each of (s) may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH)2, -Si(CH3)3, -COOH, -CONH2, -P(O)(OH) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C1-C ₄ alkylamino), C ₁ -C ₆ αlkyl ether , C1C ₄ alkylamino, C1-C ₄ hydroxyalkyl, C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

The present disclosure includes compounds and salts in which one of R ¹² and R ¹³ is hydrogen, hydroxyl, halogen, methyl or methoxy; and the other of R ¹² and R ¹³ is selected from (s), where (s) is -JP(O)(OR ²¹ )(OR ²² ), -JOP(O)(OR ²¹ )R ²² , -JP(O )(OR ²¹ )R ²² , -JOP(O)R ²¹ R ²² or -JP(O)R ²¹ R ²² ;

where J is independently selected in each case and represents a covalent bond, C1- _C4 alkylene, _C2 - _C4 alkenylene or _C2 - _C4 alkynylene;

R ²¹ and R ²² are independently selected in each case from hydrogen, hydroxyl, cyano, amino, C ₁ C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, (C ₃ -C ₇ cycloalkyl)C ₀ - C ₄ alkyl, (phenyl)C ₀ -C ₄ alkyl and -C1-C ₄ alkylOC(O)OC1-C ₆ alkyl, -C ₁ -C ₄ alkylOC(O)C ₁ -C ₆ alkyl, -C ₁ - C ₄ alkylC(O)OS ₁ -C ₆ alkyl;

each of (s) may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH)2, -Si(CH3)3, -COOH, -CONH2, -P(O)(OH) ₂ , C ₁ -C ₆ αlkyl, C ₁ -C ₆ alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C1-C ₄ alkylamino), C1C ₆ alkyl ether, C1- C ₄ alkylamino, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

The present disclosure includes compounds and salts in which one of R ¹² and R ¹³ is hydrogen, hydroxyl, halogen, methyl or methoxy; and the other of R ¹² and R ¹³ is C ₂ -C ₆ alkynylR ²³ ; Where

R ²³ represents (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl, (phenyl)C ₀ -C ₄ alkyl, (pyrrolidinyl)C ₀

- 204 043505

C ₄ alkyl, (morpholinyl)C ₀ -C ₄ alkyl, (thiomorpholinyl)C ₀ -C ₄ alkyl, (piperidinyl)C ₀ -C ₄ alkyl, (piperazinyl)C ₀ -C ₄ alkyl, (tetrahydrofuranyl)C ₀ - C ₄ alkyl, (pyrazolyl)C ₀ -C ₄ alkyl, (thiazolyl)C ₀ -C ₄ alkyl, (triazolyl)C ₀ -C ₄ alkyl, (tetrazolyl)Co-C ₄ alkyl, (imidazolyl)C ₀ -C ₄ alkyl, (oxazolyl)C ₀ -C ₄ alkyl, (furanyl)C ₀ -C ₄ alkyl, (pyridinyl)C ₀ -C ₄ alkyl, (pyrimidinyl)C ₀ -C ₄ alkyl, (pyrazinyl)C ₀ -C ₄ alkyl, (pyridizinyl)C ₀ C ₄ alkyl and (tetrahydropyridinyl) C ₀ -C ₄ alkyl; which may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH) ₂ , -Si( _CH3 ) ₃ , -COOH, -CONH2, -P( O)(OH) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C ₁ -C ₄ alkylamino), C ₁ -C ₆ alkyl ether, C1 -C ₄ alkylamino, C 1 -C ₄ hydroxyalkyl, C ₁ -C ₂ haloalkyl and C 1 -C ₂ haloalkoxy.

The present disclosure includes compounds and salts in which one of R ¹² and R ¹³ is hydrogen, hydroxyl, halogen, methyl or methoxy; and the other of R ¹² and R ¹³ is selected from (s), where (s) is selected from -JNR ⁹ C(O)OR ¹⁰ , -JNR ⁹ C(O)OR ²³ , -JOC(O)NR ²¹ R ²² , JOC(O)NR ²⁴ R ²⁵ , JNR ⁹ C(O)NR ¹⁰ R ²³ and -JNR ⁹ C(O)NR ²⁴ R ²⁵ ;

R ²¹ and R ²² are independently selected in each case from hydrogen, hydroxyl, cyano, amino, C ₁ C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, (C ₃ -C ₇ cycloalkyl)C ₀ - C ₄ alkyl, (phenyl)C ₀ -C ₄ alkyl, -C ₁ C ₄ alkylOC(O)OC1-C ₆ alkyl, -C1-C ₄ alkylOC(O)C1-C ₆ alkyl, -C ₁ -C ₄ alkylC(O)OS _{1 -C6} alkyl, (pyrrolidinyl)C0-C4alkyl, (morpholinyl)C0-C4alkyl, (thiomorpholinyl)C0-C4alkyl, (piperidinyl)C0C4alkyl, (piperazinyl)C0-C4alkyl, (tetrahydrofuranyl)C0-C4alkyl , (pyrazolyl)C0-C4 alkyl, (thiazolyl)C ₀ -C ₄ alkyl, (triazolyl)C ₀ -C ₄ alkyl, (tetrazolyl)C ₀ -C ₄ alkyl, (imidazolyl)C ₀ -C ₄ alkyl, (oxazolyl )C ₀ -C ₄ alkyl, (furanyl)C ₀ -C ₄ alkyl, (pyridinyl)C ₀ -C ₄ alkyl, (pyrimidinyl)C ₀ -C ₄ alkyl, (pyrazinyl)C0-C4 alkyl, (pyridizinyl)C0- C4alkyl and (tetrahydropyridinyl)C0-C4alkyl;

R ²³ is independently selected in each case from (C3-C7cycloalkyl)C0-C4-alkyl, (phenyl)C0-C4alkyl, (pyrrolidinyl) _C0 - _C4 alkyl, (morpholinyl) _C0 - _C4 alkyl, (thiomorpholinyl)C ₀ -C ₄ alkyl, (piperidinyl)C ₀ C ₄ alkyl, (piperazinyl)C ₀ -C ₄ alkyl, (tetrahydrofuranyl)C ₀ -C ₄ alkyl, (pyrazolyl)C ₀ -C ₄ alkyl, (thiazolyl)C ₀ -C ₄ alkyl, (triazolyl)C ₀ -C ₄ alkyl, (tetrazolyl)C ₀ -C ₄ alkyl, (imidazolyl)C ₀ -C ₄ alkyl, (oxazolyl)C0-C4 alkyl, (furanyl)C0-C4 alkyl, ( pyridinyl)C0-C4 alkyl, (pyrimidinyl)C0-C4 alkyl, (pyrazinyl)C ₀ -C ₄ alkyl, (pyridizinyl)C ₀ -C ₄ alkyl and (tetrahydropyridinyl)C ₀ -C ₄ alkyl;

R ²⁴ and R ²⁵ together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl group, each of which is optionally bridged with a methylene or ethylene group or spiro with a C ₃ -C ₆ cycloalkyl group; each of (s) may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH) ₂ , -Si(CH ₃ ) ₃ , -COOH, -CONH ₂ , -P(O)(OH) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C1-C ₄ alkylamino), C ₁ -C ₆ alkyl ethers, C ₁ C ₄ alkylamino, C 1 -C ₄ hydroxyalkyl, C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy.

The present invention includes compounds and salts of formula IA:

HN^

R ⁶ (ΙΑ), where

B may have any of the definitions set forth herein for that variable. In some embodiments, B is 2-fluoro-3-chlorophenyl or 2-fluoro-3-trifluoromethoxyphenyl. Examples of such compounds include those presented in table. 1. In any of the compounds shown in table. The 1,2-fluoro-3-chlorophenyl group can be replaced by 2fluoro-3-trifluoromethoxyphenyl.

The present disclosure includes compounds and salts of formula IB, IC and ID.

In the formula, the IB, IC and ID variables may include any of the definitions set forth herein that results in the formation of a stable compound. In some embodiments, the following conditions apply to claims IB, IC, and ID.

R ¹ represents hydrogen and R ² represents fluorine.

R ¹ and R ² are connected to form a 3-membered ring.

- 205 043505 m is equal to 0.

B is pyridyl, optionally substituted with halogen, C1-C2 alkoxy and trifluoromethyl.

B is phenyl substituted with 1, 2 or 3 substituents independently selected from halogen, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, trifluoromethyl and optionally substituted phenyl.

R ¹³ represents hydrogen, and R ¹² represents -NHC(O)NR ²⁴ R ²⁵ .

R ¹³ represents hydrogen and R ¹² represents -CCR ²³ .

R ¹³ represents hydrogen, and R ¹² represents -NHC(O)NHR ²³ .

R ¹³ represents hydrogen, and R ¹² represents -C(O)R ²³ .

Embodiments.

Option 1. Compound of Formula I

and its pharmaceutically acceptable salts, where

Q ¹ represents N(R1) or C(R1R1);

^Q2 is C( ^R2R2 '), C( ^R2R2 ')-C( ^R2R2 '), S, O, ^{N(R2 ) or C} (R2R22')O;

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

X ¹ and X ² independently represent N or CH, or X ¹ and X ² together represent C=C;

R ¹ , R ¹ , R ² , R ² , R ³ and R ³ are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2- C6alkynyl, C2-C6alkanoyl, C1C6thioalkyl, hydroxyC1-C6alkyl, aminoC1-C6alkyl, -C0-C4alkyl-NR ⁹ R ¹⁰ , -C(O)OR ⁹ , -OC(O)R ⁹ , NR ⁹ C(O)R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ , -NR ⁹ C(O)OR ¹⁰ , C1-C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy, where R ⁹ and R ¹⁰ independently selected in each case from hydrogen, C ₁ -C ₆ alkyl, (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl) and -O-C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl);

A represents a group selected from:

- 206 043505

each of R ⁴ other than hydrogen, -CHO and -CONH2 is unsubstituted or substituted by one or more of amino, imino, halogen, hydroxyl, cyano, cyanoimino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy,

-C ₀ -C ₂ alkyl (mono- and di-C1-C ₄ alkylamino), C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy;

R ⁵ and R ⁶ are independently selected from -CHO, -C(O)NH2, -C(O)NH(CH3), C2-C6alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, -COOH, -SO2NH2, vinyl, C1-C6alkyl (including methyl), C2C6alkenyl, C1-C6alkoxy, -C0-C4alkyl(C3-C7cycloalkyl), -C(O)C0-C4alkyl(C3-C7cycloalkyl), -P(O)(OR ⁹ ) 2, -OC(O)R ⁹ , -C(O)OR ⁹ , C(O)N(CH ₂ CH ₂ R ⁹ )(R ¹⁰ ), -NR ⁹ C(O)R ¹⁰ , phenyl or 5- 6-membered heteroaryl; and wherein each R ⁵ and R ⁶ other than hydrogen, hydroxyl, cyano and -COOH is unsubstituted or optionally substituted;

R ⁶ is hydrogen, halogen, hydroxyl, C1- _C4 alkyl, _-C0 - _C4 alkyl ( _C3 - _C7 cycloalkyl) or C1- _C4 alkoxy; or R ⁶ and R ⁶ can be taken together to form an oxo, vinyl or imino group;

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

R8 and R8 are independently selected from hydrogen, halogen, hydroxyl, _C1 - _C6 alkyl, _-C0 - _C4 alkyl( _{C3C7 cycloalkyl} ), _C1 - _C6 alkoxy and (C1- _C4 alkylamino) _C0 -C ₂ alkyl; or R8 and R8 taken together form an oxo group; or R8 and R8 may be taken together with the carbon atom to which they are bonded to form a 3-membered carbocyclic ring;

R ¹⁶ is absent or may include one or more substituents independently selected from halo, hydroxyl, nitro, cyano, C1-Cbalkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkanoyl, _C1 - _C6 alkoxy , -C ₀ C ₄ alkyl (mono- and di-C1-C ₆ alkylamino), -C ₀ -C ₄ alkyl (C ₃ -C7cycloalkyl), C1-C ₂ haloalkyl and C1C ₂ haloalkoxy;

R ¹⁹ represents hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, -SO2C1-C6alkyl, (mono-di-C1-C6alkylamino)C1-C4alkyl, -C0-C4alkyl(C3-C7cycloalkyl), -C0-C4alkyl( C3-C7heterocycloalkyl), -C0-C4alkyl(aryl), C0-C4alkyl(heteroaryl), and where R ¹⁹ other than hydrogen is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, -COOH and -C(O)OC1-C4alkyl;

X ¹¹ represents N or CR ¹¹ ;

X ¹² represents N or CR ¹² ;

X ¹³ represents N or CR ¹³ ,

X ¹⁴ is N or CR ¹⁴ , and wherein no more than 2 of X ¹¹ , X ¹² , X ¹³ and X ¹⁴ are N;

one of R ¹² and R ¹³ is selected from R ³¹ , and the other of R ¹² and R ¹³ is selected from R ³² :

R ³¹ is selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, -COOH, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C6alkyl, -C0-C4alkyl(C3-C7cycloalkyl), C2-C6alkenyl, C2-C6alkanoyl, C1C6alkoxy , C2-C6alkenyloxy, -C(O)OR ⁹ , C1-C ₆ thioalkyl, -C ₀ -C ₄ αlkyl-NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO2R ⁹ , -SO2NR9R ¹⁰ , -OC(O)R ⁹ and -C(NR ⁹ )NR ⁹ R ¹⁰ , each of R ³¹ other than hydrogen, halogen, hydroxyl, nitro, cyano, C1-C2haloalkyl and C1-C2haloalkoxy, is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, COOH, -CONH2 C1-C2haloalkyl and C1-C2haloalkoxy, and each of R ³¹ is also optionally substituted with one substituent selected from phenyl and a 4-7 membered heterocycle, containing 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein the phenyl or 4-7-membered heterocycle is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C1-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkoxy, (mono- and di-C1C ₆ alkylamino) Co-C ₄ alkyl, C ₁ -C ₆ alkyl ether, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C ₁ - C ₂ haloalkyl and C 1 -C ₂ haloalkoxy;

R ³² is selected from aryl; a saturated or unsaturated heterocycle, where the heterocycle is linked through a carbon atom in the heterocyclic ring to the carbon atom of ring A at position R ¹² or R ¹³ ; and heteroaryl, wherein the aryl, heterocycle or heteroaryl ring may be optionally substituted.

R ¹¹ , R ¹⁴ and R ¹⁵ are independently selected in each case from hydrogen, halogen, hydroxyl, nitro, cyano, -O(PO)(OR ⁹ )2, -(PO)(OR ⁹ )2, C ₁ -C ₆ αlkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ alkanoyl, C1C ₆ alkoxy, C ₁ -C ₆ thioalkyl, -C ₀ -C ₄ alkyl (mono- and di-C ₁ - C ₆ alkylamino), -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -C ₀ -C ₄ alkoxy (C ₃ -C ₇ cycloalkyl), C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy ;

R ²¹ and R ²² are independently selected in each case from hydrogen, hydroxyl, cyano, amino, C1C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl, (phenyl)C ₀ -C ₄ alkyl, -C1C ₄ alkylOC(O)OC1-C ₆ alkyl, -C ₁ -C ₄ alkylOC(O)C ₁ -C ₆ -alkyl, -C ₁ -C ₄ alkylC (O)OC ₁ -C ₆ alkyl, (4-7 membered heterocycloalkyl)C0-C4 alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S, and (5- or 6-membered unsaturated or aromatic heterocycle) C ₀ -C ₄ -alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S, and each of R ²¹ and R ²² may be optionally substituted;

R ²³ is independently selected in each case from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, (aryl)C ₀ -C ₄ alkyl, (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl, (phenyl) C ₀ -C ₄ alkyl, (4-7 membered heterocycloalkyl)C ₀ -C ₄ alkyl having 1, 2, or 3 heteroatoms independently selected from N, O and S, and (5- or 6-membered unsaturated or an aromatic heterocycle)C0-C4alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and each R ²³ may be optionally substituted;

R ²⁴ and R ²⁵ together with the nitrogen atom to which they are attached form a 4-7 membered monocyclic heterocycloalkyl group or a 6-10 membered bicyclic heterocyclic group having fused, spiro or bridged rings, and each of R ²⁴ and R ²⁵ may optionally be substituted;

R ³⁰ is independently selected in each case from hydrogen, C1-C6alkyl, C1-C6haloalkyl, (aryl)C0C4alkyl, (C3-C7cycloalkyl)C0-C4alkyl, (phenyl)C0-C4alkyl, (4-7 membered heterocycloalkyl)C0C4alkyl, having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and a (5- or 6-membered unsaturated or aromatic heterocycle)C0-C4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; COOH, Si(CH3)3, COOR ^30a , C2-C ₆ alkanoyl, -B(OH) ₂ , -C(O)(CH ₂ )1- ₄ S(O)R ²¹ , -P(O)(OR ²¹ )(OR ²² ), -P(O)(OR ²¹ )R ²² , -P(O)R ²¹ R ²² , -NR ⁹ P(O)(NHR ²¹ )(NHR ²² ), -NR ⁹ P( O)(OR ²¹ )(NHR ²² ), -NR ⁹ P(O)(OR ²¹ )(OR ²² ), -C(S)R ²¹ , -NR ²¹ SO2R ²² , -NR ⁹ S(O)NR ¹⁰ R ²² , -NR ⁹ SO2NR ¹⁰ R ²² , -SO2NR ⁹ COR ²² , -SO2NR ⁹ CONR ²¹ R ²² , -NR ²¹ SO2R ²² , -C(O)NR ²¹ SO2R ²² , -C(NH2)NR ⁹ R ²² , -C(NH2)NR ⁹ S(O)2R ²² , -NR ⁹ C(O)OR ¹⁰ , -NR ²¹ OC(O)R ²² , -(CH2)i-4C(O)NR ²¹ R ²² , -C(O)R ²⁴ R ²⁵ , -NR ⁹ C(O)R ²¹ , -C(O)R ²¹ , -NR ⁹ C(O)NR ⁹ R ¹⁰ , -NR ⁹ C(O)NR ²⁴ R ²⁵ , -(CH ₂ )1. ₄ OC(O)R ²¹ , each R ³⁰ may be optionally substituted;

R ^30a represents C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl-, (aryl)C ₀ -C ₄ alkyl -, (3-7-membered heterocycloalkyl)C ₀ -C ₄ alkyl-, having 1, 2 or 3 heteroatoms independently selected from N, O and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C ₀ - 208 043505

With ₄ alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S, each R ^30a may be optionally substituted;

L represents a bond or is selected from formulas

where R ¹⁷ represents hydrogen, C ₁ -C ₆ alkyl or -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), and R ¹⁸ and R ¹⁸ are independently selected from hydrogen, halogen, hydroxymethyl and methyl; and m is 0, 1, 2 or 3;

B is a monocyclic or bicyclic carbocyclic; a monocyclic or bicyclic carbocyclooxy 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 in the ring; C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl; -(C ₀ -C ₄ -alkyl)(aryl); -(C ₀ -C ₄ alkyl)(heteroaryl); or -(C ₀ -C ₄ -alkyl)(biphenyl) each of B is unsubstituted or substituted with one or more substituents independently selected from R ³³ and R ³⁴ , and 0 or 1 substituent selected from R ³⁵ and R ³⁶ ;

R ³³ is independently selected from halogen, hydroxyl, -COOH, cyano, O1-C6alkyl, C2-C6alkanoyl, C1C6alkoxy, -C0-C4alkyl-NR ⁹ R ¹⁰ , -SO2R ⁹ , C1-C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy ;

R ³⁴ is independently selected from nitro, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ thioalkyl, -JC3C7cycloalkyl, -B(OH) ₂ , -JC(O)NR ⁹ R ²³ , -JOSO2OR ²¹ , -C(O)(CH2)1-4S(O)R ²¹ , -O(CH2)1-4S(O)NR ²¹ R ²² , -JOP(O)(OR ²¹ )(OR ²² ), - JP(O)(OR ²¹ )(OR ²² ), -JOP(O)(OR ²¹ )R ²² , JP(O)(OR ²¹ )R ²² , -JOP(O)R ²¹ R ²² , -JP(O )R ²¹ R ²² , -JSP(O)(OR ²¹ )(R ²² ), -JSP(O)(OR ²¹ )(R ²² ), -JSP(O)(R ²¹ )(R ²² ), -JNR ⁹ P(O)(NHR ²¹ )(NHR ²² ),

-JNR ⁹ P(O)(OR ²¹ )(NHR ²² ), JNR ⁹ P(O)(OR ²¹ )(OR ²² ), -JC(S)R ²¹ , -JNR ²¹ SO2R ²² , -JNR ⁹ S( O)NR ¹⁰ R ²² , -JNR ⁹ SO2NR ¹⁰ R ²² , -JSO2NR ⁹ COR ²² , -JSO2NR ⁹ CONR ²¹ R ²² , -JNR ²¹ SO2R ²² , -JC(O)NR ²¹ SO2R ²² , -JC(NH2) NR ²² , -JC(NH2)NR ⁹ S(O)2R ²² , -JOC(O)NR ²¹ R ²² , -JNR ²¹ C(O)OR ²² , -JNR ²¹ OC(O)R ²² , -(CH2 )1-4C(O)NR ²¹ R ²² , -JC(O)R ²⁴ R ²⁵ , -JNR ⁹ C(O)R ²¹ , -JC(O)R ²¹ , -JNR ⁹ C(O)NR ¹⁰ R ²² , -CCR ²¹ , -(CH2)1-4OC(O)R ²¹ and -JC(O)OR ²³ ; each of R ³⁴ may be unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH) ₂ , -Si(CH ₃ ) ₃ , -COOH, -CONH2, -P(O)(OH) ₂ , C ₁ -C ₆ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C ₆ alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C ₁ -C ₄ alkylamino), C ₁ -C ₆ alkyl ether, C ₁ -C ₄ alkylamino, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy;

R ³⁵ is independently selected from naphthyl, naphthyloxy, indanyl, (4-7 membered heterocycloalkyl)C0C4alkyl containing 1 or 2 heteroatoms selected from N, O and S, and a bicyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and containing from 4 to 7 ring atoms in each ring; each of R ³⁵ is unsubstituted or substituted by _one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C1- _C6 alkyl, _C2 - _C6 alkenyl, _C2C6 alkanoyl, _C1 - _C6 alkoxy, ( mono- and di-C ₁ -C ₆ alkylamino)C ₀ -C ₄ alkyl, C ₁ -C ₆ alkyl ether, -C ₀ C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -SO2R ⁹ , C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy; And

R ³⁶ is independently selected from tetrazolyl, (phenyl)C0-C2alkyl, (phenyl)C1-C2alkoxy, phenoxy and 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, B and S, each of R ³⁶ is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C1- _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkanoyl, _C1 - _C6 alkoxy, (mono- and diC ₁ -C ₆ alkylamino)C ₀ -C ₄ alkyl, C ₁ -C ₆ alkyl ether, -C ₀ -C ₄ alkyl(C ₃ -C ₇ cycloalkyl), -SO2R ⁹ , OSi(CH ₃ ) ₂ C(CH ₃ ) ₃ , -Si(CH ₃ ) ₂ C(CH ₃ ) ₃ , C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy; And

J is independently selected in each case from a covalent bond, C ₁ -C ₄ alkylene, -OC ₁ -C ₄ alkylene, C ₂ C ₄ alkenylene and C ₂ -C ₄ alkynylene.

Option 2. A pharmaceutical composition comprising an effective amount of the compound of Option 1 in a pharmaceutically acceptable carrier.

Embodiment 3. A method of treating a complement-mediated disorder, comprising administering to a subject in need thereof an effective amount of a compound of embodiment 1, optionally in a pharmaceutically acceptable carrier.

Option 4. The method according to option 3, in which the subject is a human.

Embodiment 5. The method of embodiment 3, wherein the complement-mediated pathway is age-related macular degeneration (AMD).

Embodiment 6. The method of Embodiment 3, wherein the complement-mediated pathway is retinal degeneration.

Embodiment 7. The method of embodiment 3, wherein the complement-mediated pathway is an ophthalmic disease.

Embodiment 8. The method of embodiment 3, wherein the complement-mediated pathway is paroxysmal nocturnal hemoglobinuria (PNH).

Embodiment 9. The method of embodiment 3, wherein the complement-mediated pathway is multiple sclerosis.

Embodiment 10. The method of embodiment 3, wherein the complement-mediated pathway is arthritis.

- 209 043505

Embodiment 11. The method of embodiment 3, wherein the complement-mediated pathway is rheumatoid arthritis.

Embodiment 12. The method of embodiment 3, wherein the complement-mediated pathway is a respiratory disease or a cardiovascular disease.

Option 13. Connection according to option 1, where the ring is selected from:

where q is 0, 1, 2 or 3, and r is 1, 2 or 3;

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

Z represents F, Cl, NH ₂ , CH ₃ , CH2D or CD3.

Option 14. The compound according to option 1, where R ¹ and R ¹ or R ³ and R ³ can be taken together to form a 3-6 membered carbocyclic spiro ring or a 3-6 membered heterocyclic spiro ring containing 1 or 2 heteroatom independently selected from N, O or S.

Embodiment 15. The compound of embodiment 1, wherein R ² and R ² may be taken together to form an optionally substituted 3-6 membered carbocyclic spiro ring;

or R ² and R ² can be taken together to form a 3-6 membered heterocyclic spiro ring.

Option 16. Connection according to option 1, where -L-B- is selected from:

- 210 043505

oh! ⁸ r ¹⁸ X^R ²⁸

OR ^R 25 ;

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

m is 0 or 1; And

R ²⁶ , R ²⁷ and R ²⁸ are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, C1-C6thioalkyl, (mono- and di-C1-C6alkylamino )C0C4alkyl, (C3-C7cycloalkyl)C0-C4alkyl, (aryl)C0-C4alkyl-, (heteroaryl)C0-C4alkyl- and -C0C4alkoxy(C3-C7cycloalkyl); each of which R ²⁶ , R ²⁷ , R ²⁸ other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxyl, amino, C1-C2 alkoxy, C1-C ₂ haloalkyl, (C ₃ C ₇ cycloalkyl)C ₀ -C ₄ alkyl- and C1-C ₂ haloalkoxy; and R ²⁹ is hydrogen, C 1 -C ₂ alkyl, C ₁ C ₂ haloalkyl or -Si(CH ₃ ) ₂ C(CH ₃ ) ₃ .

Option 17. Connection according to option 1, where B is selected from:

- 211 043505

Br Cl J p Η CN Cl Λ F F ^F ~d N=( Cl F /\α To 1 I/) 0 F -'% 0 (7—p 0 CI^^^CI Ύ J ,NH yOQq F F )=( ьк Cl HnP'A F )=( /=( ^F 1 Jy HN^ZA ^F \ / \ _ nmr'A F \=( Qk F )=( /=( OCH ₃ Hy )=( SCH ₃ KJ F ci i Jy Np / f pp /=( ocH ₃ Qk F )=( /=( SCH ₃ -J K ° Cl Q w ⁰ CZ^H ₃ co pp -10 ⁰ 0 h ₃ cs pp -У ⁰ » 0 KP o L J) ^Cl op RF main ₃ 0 O J)™ About About SCH ₃ F »P Vj ^F F 0 z ρϊ OSNZ F 0 d PJCN F 0 d /uch SCH ₃ o=s^ ^CF3 _z o O ^z \—< ZA

- 212 043505

°'S ^/ > ^{Z 0} NH ⁰⁼ ( λα -A all/ ⁴ оУ ^Нз / θ 0 ^Z ---4 λα -ь^2/ ^Cl UA 1^2/ ^Cl ajDA A PG11 O O o A/ ⁰ \Ua <A CF ₃ 0 UA CH ₃ S Ua 1^2/ ¹ o / ⁰ ΛΑ A / ⁰ λα / ⁰ LA UCH ^0SNz / ° LA nA ci Yu / ⁰ ΛΑ, ^N A; ^F Yu / ⁰ ΛΑ nA cn a / ⁰ LA nA main ₃ / ⁰ n - ^CF 3 °5δ 0 ^Z —< ΛΑ nA ci -У 0=s ⁷ nA ci -Yu

- 213 043505

- 214 043505

\n^n^o ^Ν £ι Μ Η ^ν _Ν Q Η CO £ Ν ₄ K Ν Ν to 1 Υ ν Ν-Ν Ό -Ο Ου '° ην^ν ό and 0 / Οχ _z o \bsi^.F Τ Υ Υ JVVL ⁴ ιΟ BEFORE X Χν Οχ Ο Ν^Ν OL^O/S^___ ^-Ν Χ ^Ν Λ V \ /— CN Η Ν'Ν θ Ν^Ν ΐ if ΟζΧ he vQn Kommersant F jXX%° 0 ΠνΟ? Un' U5 with ^nh O Ό ο^νη ₂ 1° ^Z TXJ Τ' l ^h ^· ^{F f} b Η Όχ4γ-0 F and X O

where R ²⁷ represents hydrogen, methyl or trifluoromethyl;

R ²⁸ represents hydrogen or halogen; And

R ²⁹ is hydrogen, methyl, trifluoromethyl or -Si(CH ₃ ) ₂ C(CH ₃ ) ₃ .

Option 18. Connection according to option 1, where R ³² is selected from

- 215 043505

Embodiment 19. Use of a compound according to any one of embodiments 1, 13, 14, 15, 16, 17, or 18 for the manufacture of a medicament for the treatment of a complement Factor D-mediated disorder.

Embodiment 20. The compound of embodiment 1, 13, 14, 15, 16, 17 or 18 for use in the treatment of a complement Factor D mediated disorder.

Embodiment 21 Use as in embodiment 19, wherein the disorder is paroxysmal nocturnal hemoglobinuria (PNH).

Embodiment 22: Use as in Embodiment 19, method as in Embodiment 3, wherein the disorder is multiple sclerosis.

Embodiment 23: Use as in Embodiment 19, wherein the disorder is arthritis.

Embodiment 24: Use as in Embodiment 19, wherein the disorder is rheumatoid arthritis.

Embodiment 25: Use as in embodiment 19, wherein the disorder is a respiratory disease or a cardiovascular disease.

Embodiment 26. The compound of Embodiment 20, wherein the disorder is multiple sclerosis.

Embodiment 27: The compound of Embodiment 20, wherein the disorder is arthritis.

Embodiment 28. The compound of Embodiment 20, wherein the disorder is rheumatoid

- 216 043505 arthritis.

Embodiment 29. The compound of embodiment 20, wherein the disorder is a respiratory disease or a cardiovascular disease.

This specification has been described with reference to embodiments of the invention. However, it will be apparent to one of ordinary skill in the art that various modifications and changes can be made without departing from the scope of the present invention as set forth in the claims below. Accordingly, the description is to be considered in an illustrative and not a restrictive sense, and all such modifications are intended to be included within the scope of the invention.

Claims (19)

1. Compound of formula I or a pharmaceutically acceptable salt thereof, wherein Q ¹ represents C(R1R1); Q ² represents C(R2R ² ); Q ³ represents C(R ³ R ³ ); X ¹ represents N; X ² represents CH; R ¹ and R ² are taken together to form a 3-6 membered cycloalkyl group; R ¹ , R ² , R ³ and R ³ are each hydrogen; R ⁹ and R ¹⁰ are independently selected from hydrogen and C ₁ -C ₆ alkyl; A represents a group selected from: R ⁵ represents hydrogen; R ⁶ represents -C(0)NH2 or C ₂ -C ₆ alkanoyl; R8 and R8 represent hydrogen; X ¹¹ represents CR ¹¹ ; X ¹² represents CR ¹² ; X ¹³ represents CR ¹³ ; X ¹⁴ represents CR ¹⁴ ; one of R ¹² and R ¹³ is selected from R ³¹ and the other of R ¹² and R ¹³ is selected from R ³² ; R ³¹ represents hydrogen; R ³² is selected from: 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S; phenyl; and a saturated or unsaturated 6-membered heterocycle containing 1 or 2 nitrogen atoms, where the heterocycle is linked through a carbon atom in the heterocyclic ring to the carbon atom of ring A; and wherein each R ³² is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, cyano, hydroxyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C 1 -C ₂ haloalkyl, C ₁ -C ₆ alkylsulfonyl, a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 6-membered heterocycle containing 1 or 2 heteroatoms independently selected from N, O and S; R ¹¹ and R ¹⁴ represent hydrogen; °R ¹⁸ R ¹⁸ ' L represents _: R ¹⁷ represents hydrogen; m represents 0; B represents a monocyclic or bicyclic carbocyclic group containing from 3 to 6 ring atoms per ring; monocyclic or bicyclic heterocyclic - 217 043505 a group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and from 4 to 7 ring atoms per ring; -(C ₀ -C ₄ alkyl)(monocyclic or bicyclic aryl containing 6 ring atoms per ring); -(Co-C ₄ alkyl)(monocyclic or bicyclic heteroaryl group containing from 1 to 3 heteroatoms independently selected from N, O and S, and from 5 to 6 ring atoms per ring); or -(C ₀ -C ₄ alkyl)(biphenyl), each of B is unsubstituted or substituted with one to four substituents independently selected from R ³³ and R ³⁴ and 0 or 1 substituent selected from R ³⁵ and R ³⁶ ; R ³³ is independently selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -C0-C4anKHn-NR ⁹ R ¹⁰ , C1-C2 haloalkyl and C1-C ₂ haloalkoxy; R ³⁴ represents -3C ₃ -C ₇ cycloalkyl; R ³⁵ is independently selected from naphthyl and (4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O and 8)C0-C4 alkyl, each of R ³⁵ is unsubstituted or substituted with one substituent independently selected from halogen, hydroxyl , nitro, cyano, C1-C6 alkyl, C ₂ C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C1-C ₆ alkoxy, (mono- and di-C1-C ₆ alkylamino) C ₀ -C ₄ alkyl, complex C _g Valkyl ether, -Co-C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -SO ₂ R ⁹ , C1-C ₂ haloalkyl and C1-C ₂ haloalkoxy; R ³⁶ is independently selected from (phenyl)C0-C2alkyl, (phenyl)C1-C2alkoxy and 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, B and S, each of R ³⁶ is unsubstituted or substituted with one or two substituents independently selected from halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C1-C ₆ alkoxy, (mono- and di- CiCbalkylamino)Co-C ₄ alkyl, -Co-C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -8O ₂ alkyl, C1-C ₂ haloalkyl and CiC ₂ haloalkoxy; And J is independently selected from covalent bond, C1- _C4 alkylene, _-OC1 - _C4 alkylene, _C2 - _C4 alkenylene and _C2C4 alkynylene. il 2. The connection according to claim 1, where the ring is 3. Connection according to claim 1, where -L-B- is selected from: w represents 0 or 1; And R ²⁶ , R ²⁷ and R ²⁸ are independently selected from hydrogen, halogen, hydroxyl, C1- _C6 alkyl and C1- _C6 alkoxy; R ²⁶ , R ²⁷ and R ²⁸ other than hydrogen, halogen and hydroxyl are each unsubstituted or substituted with one or more substituents independently selected from halogen. 4. The connection according to claim 1, where B is selected from: -218043505 5. The connection according to claim 1, where R ³² is selected from 6. The connection according to claim 1, where the connection is: - 219 043505 or a pharmaceutically acceptable salt thereof. 7. A pharmaceutical composition for the treatment of a complement factor D-mediated disorder, comprising an effective amount of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier. 8. A method of treating a disorder mediated by complement factor D, which comprises administering to the host an effective amount of a compound according to any one of claims 1 to 6 or pharmaceutically - 220 043505 acceptable salt or pharmaceutical composition according to claim 7. 9. The method of claim 8, wherein the disorder is acute respiratory distress syndrome, age-related macular degeneration (AMD), arthritis, asthma, dementia of the Alzheimer's type, atypical or typical hemolytic uremic syndrome, antiphospholipid syndrome, cardiovascular disease, blistering skin disease disease, bullous pemphigoid, SZ glomerulonephritis, chronic obstructive pulmonary disease (COPD), Crohn's disease, diabetic retinopathy, epidermos bullosa, geographic atrophy, glomerulonephritis, Guillain-Barré syndrome, hemolytic anemia, hyperacute allograft rejection, ischemia-reperfusion injury, lupus nephritis, membranous proliferative glomerulonephritis, metabolic disorder, MPGN II, multiple sclerosis, myasthenia gravis, neuromyelitis optica, ocular cicatricial pemphigoid, ocular disorder, eye disease, paroxysmal nocturnal hemoglobinuria (PNH), pauci-immune vasculitis, pemphigoid, pulmonary vasculitis, retinal degeneration, respiratory disease, rheumatoid arthritis, sepsis, transplant rejection, traumatic brain injury, or vasculitis. 10. The method of claim 9, wherein the disorder is paroxysmal nocturnal hemoglobinuria (PNH). 11. The method of claim 9, wherein the disorder is retinal degeneration, multiple sclerosis, arthritis, rheumatoid arthritis, a respiratory disease, or a cardiovascular disease. 12. The method of claim 9, wherein the disorder is age-related macular degeneration. 13. The method according to claim 9, wherein the disorder is SZ glomerulonephritis. 14. The method according to claim 9, wherein the disorder is an atypical or typical hemolytic uremic syndrome. 15. The method according to claim 9, in which the violation is MPGN P. 16. The method according to claim 9, wherein the disorder is geographic atrophy. 17. The method of claim 9, wherein the disorder is myasthenia gravis. 18. The method according to claim 9, wherein the disorder is neuromyelitis optica. 19. The method according to any one of claims 8-18, in which the host is a person.